Epidemiologic studies suggest that some hormone-related risk factors in breast cancer differentially influence risk for disease subtypes classified by the status of the estrogen and progesterone receptors (ER/PR). However, it remains unclear whether human epidermal growth factor receptor 2 (HER2) or p53 expression status further differentiates these exposure-risk group associations. We evaluated the associations of oral contraceptive (OC) use and reproductive factors with incident invasive breast cancer subtypes among 1,197 population-based cases and 2,015 controls from the Los Angeles County or Detroit components of the Women's Contraceptive and Reproductive Experiences Study. Case-control comparisons by ER/PR/HER2/p53 status were conducted by multivariable polychotomous unconditional logistic regression methods. We found that OC use was not associated with any breast cancer subtype as defined by ER/PR/HER2/p53 status, except for a 2.9-fold increased risk of so-called triple-negative tumors (ER/PR/HER2) among women of 45 to 64 years of age who started OC use before age 18. Parity was associated with a decreased risk of luminal A (ER+ or PR+, HER2), luminal B (ER+ or PR+/HER2+), and ER/PR/HER2+ tumors. Age at first full-term pregnancy was positively associated with luminal A tumors among older women. Neither of these reproductive factors was associated with triple-negative tumors. Long duration of breast-feeding lowered the risk of triple-negative and luminal A tumors. p53 status did not define further differential risk patterns. Our findings offer evidence of differences in the hormone-related risk factors between triple-negative cancers and other ER/PR/HER2-defined subtypes of breast cancer. Cancer Res; 70(2); 575–87

Epidemiologic studies have suggested that some hormone-related breast cancer risk factors differentially influence breast cancer risk by estrogen receptor (ER) and progesterone receptor (PR) expression status in tumor tissue (13). However, it remains unclear whether these associations differ further by the expression status of human epidermal growth factor receptor 2 (HER2) and p53 protein (p53).

HER2, a transmembrane tyrosine kinase receptor protein, is normally involved in the signal transduction pathways that lead to cell growth and differentiation (4, 5). HER2 is overexpressed in approximately 15% to 25% of breast carcinoma specimens (68). Several epidemiologic studies have classified breast cancers as triple-negative (ER/PR/HER2), luminal A (ER+ or PR+ plus HER2), luminal B (ER+ or PR+ plus HER2+), and ER/PR/HER2+ subtype (7, 911). Triple-negative breast cancers, which are typically more aggressive and have poorer prognosis than other subtypes, are often characterized by a basal-like molecular profile (12, 13). Basal-like breast cancers, as defined by gene expression microarray analysis, exhibit overexpression of several genes in the p21 (CDKN1A) pathway that play a critical role in cell proliferation and DNA replication (MCM3, MCM4, MCM7, and MAD2L1), whereas luminal A tumors have been associated with the ER signaling pathway (14, 15). Therefore, one might expect that associations with hormone-related breast cancer risk factors would differ between triple-negative breast cancer, a proxy for basal-like breast cancer, and other breast cancer subtypes. Thus far, epidemiologic data on this topic are inconsistent (9, 11, 16).

p53, a tumor suppressor gene, inhibits the proliferation of abnormal cells (17). p53 gene mutations that occur in approximately 15% to 35% of breast carcinoma specimens (1820) may cause loss of tumor suppressor function and gain of oncogenic activity (21). Overexpression of p53 in tumor tissue is associated with the presence of the mutations, especially missense mutations, in the p53 gene (21). It has been unclear whether the overexpression status of p53 would modify the associations between hormone-related breast cancer risk factors and breast cancer risk. Three previous epidemiologic studies have examined the effects of oral contraceptive (OC) use and reproductive factors by p53 status, but none has concurrently considered the expression status of ER, PR, and HER2 (2224).

In this study, we examined whether OC use and reproductive factors differentially influenced risk for triple-negative, luminal A, luminal B, and ER/PR/HER2+ breast cancer. Further, we explored whether any differences in the associations of OC use or reproductive factors with triple-negative and luminal A breast cancer, two common subtypes, were confined to younger (35–44 years) or older (45–64 years) women. We also evaluated whether p53 expression status modified any observed differences between these two subtypes.

Subject identification

The Women's Contraceptive and Reproductive Experiences (CARE) Study is a population-based case-control study of invasive breast cancer conducted among U.S.-born White and African-American women ages 35 to 64 y who resided in one of five areas of the United States [Atlanta, Detroit, Los Angeles (LA) County, Philadelphia, or Seattle; ref. 25]. This current study is restricted to women who participated in the LA County or the Detroit Metropolitan Area, which includes Wayne, Oakland, and MacComb counties.

Case participants in the Women's CARE Study had no prior diagnosis of invasive or in situ breast cancer and were diagnosed with their first primary invasive breast cancer between June 1994 and August 1998. Control participants were women with no history of invasive or in situ breast cancer who were identified by random digit dialing. Control participants were frequency matched to the expected distribution of cases in strata defined by 5-y age groups, ethnicity (White or African-American), and residence located in the same geographic (study) region. The Women's CARE Study recruited 1,921 cases (1,072 White and 849 African-American) and 2,034 control participants (1,161 White and 873 African-American) from LA and Detroit. The interview response rates were 73.3% for cases in LA, 73.7% for controls in LA, 74.7% for cases in Detroit, and 74.1% for controls in Detroit.

The Women's CARE Study collected demographic characteristics, detailed information about OC use, complete histories of menstrual and reproductive factors, family history of breast cancer, and information pertaining to other factors from each participant during an in-person interview. Information was recorded up to a predetermined reference date for each participant, the date of diagnosis for case patients, and the date of initial telephone screening of the household for control subjects. The detailed information on OC use was collected by using a mixture of recall and recognition techniques (structured questionnaire, response cards, color pictures of all OC preparations marketed in the United States, and a life events calendar). The detailed data about OC use and breast cancer risk (26), and combined effect of OC use and hormone replacement therapy on breast cancer risk (27), appear elsewhere. All participants provided written informed consent. The study protocol was approved by the federally approved Institutional Review Boards at participating institutions.

Assessment of biomarkers

Paraffin-embedded tumor blocks were obtained for 1,333 cases (LA, 919; Detroit, 414), ∼80% of those requested. Tumor blocks were carefully reviewed and evaluated in Dr. Press' laboratory at the University of Southern California (referred to as the centralized laboratory). This laboratory was among the first to validate use of monoclonal ER antibodies (2832) and monoclonal PR antibodies (3335) for localization of ER and PR in tissue sections by immunohistochemistry and to subsequently adapt these methods to analysis of archival tissues (36, 37).

We excluded 127 case samples because tumor blocks contained only carcinoma in situ (n = 56) or no tumor tissue (n = 46), were H&E-stained tissue sections (n = 8), had insufficient tissue for assay (n = 3), or had other problems (n = 14). We successfully determined ER, PR, HER2, and p53 expression status for 1,206 case subjects (LA, 839; Detroit, 367) in the centralized laboratory. In one previous study of the association between percent mammographic density and subtypes of breast cancer, we reported on 352 of the LA cases for whom we also had mammograms (7). In a prior report comparing ER/PR status from the centralized pathology laboratory with the classification obtained from a population-based cancer surveillance registry, we reported on concordance for ER and PR status between the two sources for 919 cases (38).

The status of ER and PR was determined using previously published immunohistochemistry methods (31, 36). Immunostaining results for ER and PR expression were interpreted in a blinded fashion and scored semiquantitatively based on the visually estimated percentage of positively stained tumor cell nuclei. The intensity of nuclear staining was scored for individual tumor cell nuclei as negative (−)/no staining, plus one (+1)/weak intensity, plus two (+2)/intermediate intensity, or plus three (+3)/strong intensity. A minimum of 100 tumor cells was scored with the percentage of tumor cell nuclei in each category recorded. In this study, an overall score of ≥1% immunostained tumor cell nuclei was considered positive for ER or PR status.

HER2 expression status was determined by immunohistochemistry using the 10H8 monoclonal antibody (8, 39) to assess HER2 membrane protein immunostaining. No immunostaining (0) or weak (1+) membrane immunostaining was considered low HER2 expression (HER2). Moderate (2+) or strong membrane immunostaining (3+) was considered HER2 overexpression (HER2+).

The expression status of p53 was determined by immunohistochemistry using the monoclonal mouse antibodies DO7 (Oncogene Science, Inc.) and BP 53-12-1 (Biogenex) to measure p53 nuclear protein immunostaining. Based on previous study findings comparing p53 mutations in exons 2 to 11 with p53 expression levels (40, 41), any nuclear staining for p53 was deemed positive (42).

Statistical analysis

We used t tests to evaluate differences in continuous variables and Pearson χ2 tests to evaluate differences in the frequency distributions of categorical variables comparing case patients with control subjects.

We assessed the association of triple-negative, ER/PR/HER2+, luminal A, and luminal B breast cancer with the following factors: OC use (never, ever), duration of OC use, age at first OC use, duration between menarche and first OC use, time since last OC use to reference date, number of full-term (>26-wk gestation) pregnancies, age at first full-term pregnancy (defined for each woman as the age at which that pregnancy ended), and duration of breast-feeding. We estimated odds ratios (OR) and corresponding 95% confidence intervals (95% CI) using multivariable polychotomous unconditional logistic regression for case-control comparisons.

Tests for trend were conducted by fitting ordinal values corresponding to exposure categories and testing whether the slope coefficient differed from zero. We also conducted Wald χ2 tests for homogeneity of the associations with OC use or reproductive factors across breast cancer subtypes by fitting a multivariable polychotomous unconditional logistic regression model for dichotomous or ordinal variables.

We included the following factors, selected a priori, as potential confounders in all multivariable models: study site (LA or Detroit), race (white or African-American), education as a proxy for social economic status (high school or lower level of education, technical school or some college, or college graduate), age (35–39, 40–44, 45–49, 50–54, 55–59, or 60–64 y), family history of breast cancer [first degree (mother, sister, or daughter); no first-degree family history including 4% of participants with uncertain answers], age at menarche (≤11, 12, 13, >13 y), menopausal status (premenopausal, postmenopausal, unknown), and body mass index (BMI) 5 y before the reference date (continuous variable, kg/m2). We also included parity (nulligravid, pregnant but no full-term pregnancy, or parity 1, 2, 3, ≥4) in models as a potential confounder when it was not the exposure of interest. When parity was the exposure of interest, we chose women who had never been pregnant as our reference group and treated women who had been pregnant but had never carried to term as a separate group that was excluded when testing for trend across categories of parity. When restricting analyses to parous women, a single model was fit to assess the joint effects of age at first full-term pregnancy and breast-feeding duration.

Using two major subtypes, triple-negative and luminal A breast cancer, we explored whether any differences in the associations of OC use or reproductive factors were confined to younger (35–44 y) or older (45–64 y) women. We also evaluated whether p53 expression status modified any observed differences between these two subtypes.

We excluded 19 control subjects and 9 case patients from the analyses who were missing information on OC use (6 controls, 4 cases), BMI (9 controls, 4 cases), or parity (4 controls, 1 case). This resulted in 2,015 controls and 1,197 cases available for the current analysis. Of the 1,197 cases, 28.0% were triple-negative, 8.1% were ER/PRHER2+, 53.9% were luminal A, and 10.0% were luminal B breast cancer. Among 335 cases with triple-negative breast cancer, 45.1% were p53+, whereas among 645 cases with luminal A breast cancer, 29.2% were p53+ breast cancer.

In reporting the results of trend tests or homogeneity tests, we considered a two-sided P value of <0.05 as statistically significant. All analyses were performed using the SAS statistical package (version 9.2; SAS Institute).

Characteristics of controls and cases

As previously reported among all participants of the Women's CARE Study (26, 43, 44), there were no differences in the OC use characteristics between case and control patients; in contrast, case participants were more likely to have a first-degree breast cancer family history (Pχ2 < 0.0001), to have fewer full-term pregnancies (Pt test = 0.008), and to have never breast-fed (Pχ2 = 0.02) compared with control participants (Supplementary Table S1).

Associations with subtypes defined by ER/PR/HER2

Examination of multiple aspects of OC use (ever use, duration of use, age at first use, interval between age at menarche and age at first OC use, and time since last OC use to reference date) showed that OC use was not associated with any subtype defined by ER, PR, and HER2 (Table 1).

Table 1.

Multivariable adjusted OR and 95% CI for invasive breast cancer associated with OC use by expression status of ER, PR, and HER2

No. controlsNo. casesOR (95% CI)
Triple negativeER/PR/HER2+Luminal ALuminal BTriple negativeER/PR/HER2+Luminal ALuminal B
OC use 
    Never use 410 59 19 155 21 Reference Reference Reference Reference 
    Ever use 1,605 276 78 490 99 1.00 (0.72–1.39) 1.21 (0.69–2.11) 0.93 (0.74–1.17) 1.23 (0.73–2.10) 
    Test for homogeneity P 0.65    
Duration of use (y) 
    <1 358 57 18 116 21 0.94 (0.63–1.42) 1.22 (0.61–2.43) 0.98 (0.73–1.32) 1.17 (0.62–2.24) 
    1–4 540 86 25 179 29 0.93 (0.63–1.36) 1.15 (0.59–2.23) 1.04 (0.79–1.37) 1.12 (0.60–2.07) 
    5–9 396 75 13 101 29 1.12 (0.75–1.66) 0.86 (0.40–1.85) 0.78 (0.57–1.06) 1.50 (0.80–2.78) 
    ≥10 311 58 22 94 20 1.06 (0.70–1.61) 1.59 (0.81–3.10) 0.87 (0.63–1.19) 1.20 (0.62–2.32) 
    Trend P      0.48 0.39 0.14 0.39 
    Test for homogeneity of trends P 0.18    
Age at first use (y) 
    ≥25 399 54 21 136 22 0.99 (0.66–1.48) 1.26 (0.66–2.42) 0.91 (0.69–1.20) 1.07 (0.57–2.00) 
    20–24 569 89 28 194 34 0.96 (0.65–1.42) 1.31 (0.68–2.55) 1.03 (0.78–1.36) 1.26 (0.68–2.34) 
    18–19 332 62 17 80 26 1.00 (0.65–1.55) 1.13 (0.53–2.42) 0.78 (0.55–1.11) 1.66 (0.84–3.27) 
    <18 305 71 12 80 17 1.12 (0.72–1.74) 0.85 (0.36–2.00) 0.89 (0.62–1.28) 1.23 (0.57–2.64) 
    Trend P      0.61 0.80 0.36 0.33 
    Test for homogeneity of trends P 0.49    
Duration between menarche and first use (y) 
    <5 264 58 12 62 13 1.01 (0.63–1.60) 0.88 (0.37–2.11) 0.78 (0.53–1.16) 1.11 (0.49–2.53) 
    5–9 662 119 41 188 53 0.96 (0.66–1.40) 1.61 (0.84–3.10) 0.87 (0.65–1.16) 1.72 (0.94–3.14) 
    10–14 437 64 13 152 21 0.99 (0.66–1.47) 0.85 (0.40–1.79) 1.01 (0.77–1.34) 1.02 (0.53–1.94) 
    ≥15 242 35 12 88 12 1.09 (0.69–1.72) 1.31 (0.61–2.78) 0.94 (0.68–1.29) 1.00 (0.47–2.09) 
    Trend P      0.89 0.55 0.99 0.90 
    Test for homogeneity of trends P 0.96    
Time since last use (y) 
    <5 165 29 44 10 0.84 (0.50–1.44) 1.57 (0.62–4.01) 0.78 (0.51–1.20) 1.13 (0.48–2.69) 
    5–9 116 27 39 1.13 (0.66–1.95) 1.63 (0.61–4.35) 1.10 (0.70–1.72) 1.40 (0.56–3.49) 
    10–14 219 45 13 68 14 1.04 (0.65–1.65) 1.44 (0.64–3.23) 0.99 (0.69–1.43) 1.27 (0.59–2.70) 
    15–19 327 51 11 86 25 0.87 (0.56–1.34) 0.92 (0.41–2.07) 0.83 (0.60–1.15) 1.62 (0.85–3.11) 
    ≥20 778 124 38 253 42 1.05 (0.74–1.48) 1.18 (0.65–2.14) 0.95 (0.74–1.21) 1.12 (0.64–1.97) 
    Trend P      0.80 0.95 0.71 0.55 
    Test for homogeneity of trends P 0.89    
No. controlsNo. casesOR (95% CI)
Triple negativeER/PR/HER2+Luminal ALuminal BTriple negativeER/PR/HER2+Luminal ALuminal B
OC use 
    Never use 410 59 19 155 21 Reference Reference Reference Reference 
    Ever use 1,605 276 78 490 99 1.00 (0.72–1.39) 1.21 (0.69–2.11) 0.93 (0.74–1.17) 1.23 (0.73–2.10) 
    Test for homogeneity P 0.65    
Duration of use (y) 
    <1 358 57 18 116 21 0.94 (0.63–1.42) 1.22 (0.61–2.43) 0.98 (0.73–1.32) 1.17 (0.62–2.24) 
    1–4 540 86 25 179 29 0.93 (0.63–1.36) 1.15 (0.59–2.23) 1.04 (0.79–1.37) 1.12 (0.60–2.07) 
    5–9 396 75 13 101 29 1.12 (0.75–1.66) 0.86 (0.40–1.85) 0.78 (0.57–1.06) 1.50 (0.80–2.78) 
    ≥10 311 58 22 94 20 1.06 (0.70–1.61) 1.59 (0.81–3.10) 0.87 (0.63–1.19) 1.20 (0.62–2.32) 
    Trend P      0.48 0.39 0.14 0.39 
    Test for homogeneity of trends P 0.18    
Age at first use (y) 
    ≥25 399 54 21 136 22 0.99 (0.66–1.48) 1.26 (0.66–2.42) 0.91 (0.69–1.20) 1.07 (0.57–2.00) 
    20–24 569 89 28 194 34 0.96 (0.65–1.42) 1.31 (0.68–2.55) 1.03 (0.78–1.36) 1.26 (0.68–2.34) 
    18–19 332 62 17 80 26 1.00 (0.65–1.55) 1.13 (0.53–2.42) 0.78 (0.55–1.11) 1.66 (0.84–3.27) 
    <18 305 71 12 80 17 1.12 (0.72–1.74) 0.85 (0.36–2.00) 0.89 (0.62–1.28) 1.23 (0.57–2.64) 
    Trend P      0.61 0.80 0.36 0.33 
    Test for homogeneity of trends P 0.49    
Duration between menarche and first use (y) 
    <5 264 58 12 62 13 1.01 (0.63–1.60) 0.88 (0.37–2.11) 0.78 (0.53–1.16) 1.11 (0.49–2.53) 
    5–9 662 119 41 188 53 0.96 (0.66–1.40) 1.61 (0.84–3.10) 0.87 (0.65–1.16) 1.72 (0.94–3.14) 
    10–14 437 64 13 152 21 0.99 (0.66–1.47) 0.85 (0.40–1.79) 1.01 (0.77–1.34) 1.02 (0.53–1.94) 
    ≥15 242 35 12 88 12 1.09 (0.69–1.72) 1.31 (0.61–2.78) 0.94 (0.68–1.29) 1.00 (0.47–2.09) 
    Trend P      0.89 0.55 0.99 0.90 
    Test for homogeneity of trends P 0.96    
Time since last use (y) 
    <5 165 29 44 10 0.84 (0.50–1.44) 1.57 (0.62–4.01) 0.78 (0.51–1.20) 1.13 (0.48–2.69) 
    5–9 116 27 39 1.13 (0.66–1.95) 1.63 (0.61–4.35) 1.10 (0.70–1.72) 1.40 (0.56–3.49) 
    10–14 219 45 13 68 14 1.04 (0.65–1.65) 1.44 (0.64–3.23) 0.99 (0.69–1.43) 1.27 (0.59–2.70) 
    15–19 327 51 11 86 25 0.87 (0.56–1.34) 0.92 (0.41–2.07) 0.83 (0.60–1.15) 1.62 (0.85–3.11) 
    ≥20 778 124 38 253 42 1.05 (0.74–1.48) 1.18 (0.65–2.14) 0.95 (0.74–1.21) 1.12 (0.64–1.97) 
    Trend P      0.80 0.95 0.71 0.55 
    Test for homogeneity of trends P 0.89    

NOTE: Triple negative, ER/PR/HER2; luminal A, ER+ or PR+ plus HER2; luminal B, ER+ or PR+ plus HER2+. Adjusted for study site, race, education, age, family history of breast cancer, age at menarche, menopausal status, BMI, and parity.

Number of full-term pregnancies was not associated with risk of triple-negative breast cancer (Ptrend = 0.84) but was inversely associated with risk of the other three subtypes (all Ptrend < 0.05; Table 2). The difference in trends across the four subtypes of breast cancer was marginally statistically significant (homogeneity test: P = 0.06).

Table 2.

Multivariable adjusted OR and 95% CI for invasive breast cancer associated with reproductive history by expression status of ER, PR, and HER2

No. controlsNo. casesOR (95% CI)
Triple negativeER/PR/HER2+Luminal ALuminal BTriple negativeER/PR/HER2+Luminal ALuminal B
No. full-term pregnancies 
    Never pregnant 176 28 83 14 Reference Reference Reference Reference 
    1 314 55 22 109 29 0.98 (0.60–1.62) 1.07 (0.47–2.41) 0.80 (0.56–1.14) 1.17 (0.59–2.31) 
    2 574 106 27 187 34 1.12 (0.71–1.78) 0.75 (0.34–1.64) 0.73 (0.53–1.00) 0.79 (0.41–1.52) 
    3 391 56 18 115 18 0.91 (0.55–1.50) 0.69 (0.30–1.60) 0.65 (0.46–0.92) 0.61 (0.29–1.29) 
    ≥4 402 63 15 104 18 1.00 (0.60–1.67) 0.47 (0.19–1.15) 0.55 (0.38–0.79) 0.55 (0.26–1.20) 
    Trend P      0.84 0.02 0.0006 0.01 
    Test for homogeneity of trends P 0.06    
    Only non–full-term pregnancy 158 27 47 0.91 (0.51–1.63) 0.67 (0.23–1.94) 0.66 (0.43–1.00) 0.55 (0.22–1.42) 
Age at first full-term pregnancy* (y) 
    ≤19 583 103 26 139 28 Reference Reference Reference Reference 
    20–24 614 91 34 195 42 0.92 (0.66–1.27) 1.34 (0.76–2.34) 1.20 (0.92–1.56) 1.42 (0.84–2.41) 
    25–29 279 45 14 124 18 1.01 (0.66–1.55) 1.23 (0.59–2.58) 1.71 (1.23–2.36) 1.15 (0.58–2.28) 
    ≥30 205 41 57 11 1.32 (0.80–2.17) 0.91 (0.35–2.36) 1.03 (0.67–1.57) 0.78 (0.33–1.85) 
    Trend P      0.40 0.92 0.15 0.71 
    Test for homogeneity of trends P 0.74    
Duration of breast-feeding* (mo) 
    Never 712 131 43 240 45 Reference Reference Reference Reference 
    <1 202 38 65 18 1.03 (0.69–1.54) 0.45 (0.17–1.17) 0.91 (0.66–1.26) 1.34 (0.74–2.41) 
    1–6 334 54 14 92 15 0.80 (0.56–1.15) 0.79 (0.41–1.51) 0.70 (0.53–0.94) 0.67 (0.36–1.25) 
    7–23 302 36 13 91 14 0.58 (0.38–0.89) 0.86 (0.44–1.68) 0.78 (0.58–1.05) 0.72 (0.37–1.38) 
    ≥24 131 21 27 0.80 (0.47–1.36) 1.31 (0.53–3.21) 0.55 (0.34–0.88) 0.91 (0.38–2.20) 
    Trend P      0.03 0.96 0.004 0.27 
    Test for homogeneity of trends P 0.68    
No. controlsNo. casesOR (95% CI)
Triple negativeER/PR/HER2+Luminal ALuminal BTriple negativeER/PR/HER2+Luminal ALuminal B
No. full-term pregnancies 
    Never pregnant 176 28 83 14 Reference Reference Reference Reference 
    1 314 55 22 109 29 0.98 (0.60–1.62) 1.07 (0.47–2.41) 0.80 (0.56–1.14) 1.17 (0.59–2.31) 
    2 574 106 27 187 34 1.12 (0.71–1.78) 0.75 (0.34–1.64) 0.73 (0.53–1.00) 0.79 (0.41–1.52) 
    3 391 56 18 115 18 0.91 (0.55–1.50) 0.69 (0.30–1.60) 0.65 (0.46–0.92) 0.61 (0.29–1.29) 
    ≥4 402 63 15 104 18 1.00 (0.60–1.67) 0.47 (0.19–1.15) 0.55 (0.38–0.79) 0.55 (0.26–1.20) 
    Trend P      0.84 0.02 0.0006 0.01 
    Test for homogeneity of trends P 0.06    
    Only non–full-term pregnancy 158 27 47 0.91 (0.51–1.63) 0.67 (0.23–1.94) 0.66 (0.43–1.00) 0.55 (0.22–1.42) 
Age at first full-term pregnancy* (y) 
    ≤19 583 103 26 139 28 Reference Reference Reference Reference 
    20–24 614 91 34 195 42 0.92 (0.66–1.27) 1.34 (0.76–2.34) 1.20 (0.92–1.56) 1.42 (0.84–2.41) 
    25–29 279 45 14 124 18 1.01 (0.66–1.55) 1.23 (0.59–2.58) 1.71 (1.23–2.36) 1.15 (0.58–2.28) 
    ≥30 205 41 57 11 1.32 (0.80–2.17) 0.91 (0.35–2.36) 1.03 (0.67–1.57) 0.78 (0.33–1.85) 
    Trend P      0.40 0.92 0.15 0.71 
    Test for homogeneity of trends P 0.74    
Duration of breast-feeding* (mo) 
    Never 712 131 43 240 45 Reference Reference Reference Reference 
    <1 202 38 65 18 1.03 (0.69–1.54) 0.45 (0.17–1.17) 0.91 (0.66–1.26) 1.34 (0.74–2.41) 
    1–6 334 54 14 92 15 0.80 (0.56–1.15) 0.79 (0.41–1.51) 0.70 (0.53–0.94) 0.67 (0.36–1.25) 
    7–23 302 36 13 91 14 0.58 (0.38–0.89) 0.86 (0.44–1.68) 0.78 (0.58–1.05) 0.72 (0.37–1.38) 
    ≥24 131 21 27 0.80 (0.47–1.36) 1.31 (0.53–3.21) 0.55 (0.34–0.88) 0.91 (0.38–2.20) 
    Trend P      0.03 0.96 0.004 0.27 
    Test for homogeneity of trends P 0.68    

NOTE: Triple negative, ER/PR/HER2; luminal A, ER+ or PR+ plus HER2; luminal B, ER+ or PR+ plus HER2+. Adjusted for study site, race, education, age, family history of breast cancer, age at menarche, menopausal status, and BMI.

*Also adjusted for parity and mutually adjusted for age at first full-term pregnancy and duration of breast-feeding among parous women.

Among parous women, older age at first full-term pregnancy was not associated with any subtype defined by ER, PR, and HER2 (Table 2). A statistically significant protective effect of longer duration of breast-feeding was observed for the two major subtypes: triple negative (Ptrend = 0.03) and luminal A (Ptrend = 0.004).

Associations with triple-negative and luminal A subtype by age

Analyses of triple-negative and luminal A subtype within age strata (younger women: 35–44 years and older women: 45–64 years) showed that older women who initiated OC use before age 18 years had a 2.9-fold increased risk for triple-negative tumors compared with women in the same age group who had never used OCs (OR, 2.87; 95% CI, 1.44–5.74); no such association for luminal A cancers was observed among older women (OR, 1.36; 95% CI, 0.75–2.48) or for either subtype among younger women (Table 3).

Table 3.

Multivariable adjusted OR and 95% CI for triple-negative and luminal A breast cancer associated with OC use by age

Younger (ages 35–44 y)Older (ages 45–64 y)
No. controlsNo. triple negativeNo. luminal AOR (95% CI) of triple negativeOR (95% CI) of luminal ANo. controlsNo. triple negativeNo. luminal AOR (95% CI) of triple negativeOR (95% CI) of luminal A
OC use 
    Never use 74 21 22 Reference Reference 336 38 133 Reference Reference 
    Ever use 647 133 175 0.72 (0.42–1.24) 0.97 (0.57–1.64) 958 143 315 1.25 (0.83–1.88) 0.92 (0.71–1.20) 
    Test for homogeneity P    0.38     0.18  
Duration of use (y) 
    <1 135 18 33 0.44 (0.22–0.90) 0.91 (0.48–1.72) 223 39 83 1.49 (0.91–2.45) 1.03 (0.73–1.45) 
    1–4 222 42 72 0.66 (0.36–1.22) 1.20 (0.68–2.11) 318 44 107 1.15 (0.70–1.89) 0.98 (0.70–1.35) 
    5–9 158 39 35 0.87 (0.46–1.62) 0.78 (0.42–1.45) 238 36 66 1.26 (0.75–2.12) 0.78 (0.54–1.12) 
    ≥10 132 34 35 0.92 (0.49–1.73) 0.90 (0.49–1.68) 179 24 59 1.06 (0.60–1.88) 0.85 (0.58–1.24) 
    Trend P    0.25 0.54    0.95 0.18 
    Test for homogeneity of trends P    0.16     0.36  
Age at first use (y) 
    ≥25 52 17 0.55 (0.22–1.38) 1.26 (0.60–2.66) 347 46 119 1.23 (0.77–1.95) 0.88 (0.65–1.18) 
    20–24 164 35 50 0.74 (0.39–1.40) 1.11 (0.61–2.01) 405 54 144 1.11 (0.68–1.83) 1.03 (0.74–1.42) 
    18–19 183 40 49 0.78 (0.42–1.44) 0.94 (0.52–1.70) 149 22 31 1.17 (0.62–2.20) 0.65 (0.40–1.06) 
    <18 248 50 59 0.70 (0.38–1.27) 0.82 (0.46–1.47) 57 21 21 2.87 (1.44–5.74) 1.36 (0.75–2.48) 
    Trend P    0.46 0.23    0.04 0.85 
    Test for homogeneity of trends P    0.11     0.05  
Duration between menarche and first use (y) 
    <5 200 44 46 0.75 (0.40–1.40) 0.82 (0.44–1.50) 64 14 16 1.59 (0.75–3.39) 0.79 (0.42–1.51) 
    5–9 329 64 95 0.69 (0.38–1.23) 1.02 (0.59–1.77) 333 55 93 1.28 (0.77–2.14) 0.80 (0.56–1.15) 
    10–14 93 20 25 0.76 (0.38–1.56) 0.98 (0.50–1.92) 344 44 127 1.16 (0.71–1.88) 1.02 (0.75–1.40) 
    ≥15 25 0.71 (0.24–2.16) 1.41 (0.56–3.54) 217 30 79 1.28 (0.76–2.14) 0.90 (0.64–1.26) 
    Trend P    0.42 0.45    0.48 0.81 
    Test for homogeneity of trends P    0.22     0.43  
Time since last use (y) 
    <5 130 26 38 0.68 (0.35–1.32) 0.97 (0.52–1.81) 35 0.69 (0.19–2.45) 0.39 (0.15–0.98) 
    5–9 89 23 34 0.88 (0.44–1.76) 1.35 (0.71–2.55) 27 1.13 (0.36–3.58) 0.50 (0.18–1.38) 
    10–14 153 33 35 0.76 (0.40–1.45) 0.82 (0.44–1.52) 66 12 33 1.42 (0.67–2.98) 1.35 (0.82–2.22) 
    15–19 155 31 33 0.70 (0.37–1.34) 0.78 (0.41–1.46) 172 20 53 0.96 (0.52–1.76) 0.87 (0.58–1.29) 
    ≥20 120 20 35 0.59 (0.29–1.21) 1.10 (0.58–2.08) 658 104 218 1.31 (0.87–2.00) 0.93 (0.70–1.22) 
    Trend P    0.26 0.64    0.17 0.90 
    Test for homogeneity of trends P    0.56     0.19  
Younger (ages 35–44 y)Older (ages 45–64 y)
No. controlsNo. triple negativeNo. luminal AOR (95% CI) of triple negativeOR (95% CI) of luminal ANo. controlsNo. triple negativeNo. luminal AOR (95% CI) of triple negativeOR (95% CI) of luminal A
OC use 
    Never use 74 21 22 Reference Reference 336 38 133 Reference Reference 
    Ever use 647 133 175 0.72 (0.42–1.24) 0.97 (0.57–1.64) 958 143 315 1.25 (0.83–1.88) 0.92 (0.71–1.20) 
    Test for homogeneity P    0.38     0.18  
Duration of use (y) 
    <1 135 18 33 0.44 (0.22–0.90) 0.91 (0.48–1.72) 223 39 83 1.49 (0.91–2.45) 1.03 (0.73–1.45) 
    1–4 222 42 72 0.66 (0.36–1.22) 1.20 (0.68–2.11) 318 44 107 1.15 (0.70–1.89) 0.98 (0.70–1.35) 
    5–9 158 39 35 0.87 (0.46–1.62) 0.78 (0.42–1.45) 238 36 66 1.26 (0.75–2.12) 0.78 (0.54–1.12) 
    ≥10 132 34 35 0.92 (0.49–1.73) 0.90 (0.49–1.68) 179 24 59 1.06 (0.60–1.88) 0.85 (0.58–1.24) 
    Trend P    0.25 0.54    0.95 0.18 
    Test for homogeneity of trends P    0.16     0.36  
Age at first use (y) 
    ≥25 52 17 0.55 (0.22–1.38) 1.26 (0.60–2.66) 347 46 119 1.23 (0.77–1.95) 0.88 (0.65–1.18) 
    20–24 164 35 50 0.74 (0.39–1.40) 1.11 (0.61–2.01) 405 54 144 1.11 (0.68–1.83) 1.03 (0.74–1.42) 
    18–19 183 40 49 0.78 (0.42–1.44) 0.94 (0.52–1.70) 149 22 31 1.17 (0.62–2.20) 0.65 (0.40–1.06) 
    <18 248 50 59 0.70 (0.38–1.27) 0.82 (0.46–1.47) 57 21 21 2.87 (1.44–5.74) 1.36 (0.75–2.48) 
    Trend P    0.46 0.23    0.04 0.85 
    Test for homogeneity of trends P    0.11     0.05  
Duration between menarche and first use (y) 
    <5 200 44 46 0.75 (0.40–1.40) 0.82 (0.44–1.50) 64 14 16 1.59 (0.75–3.39) 0.79 (0.42–1.51) 
    5–9 329 64 95 0.69 (0.38–1.23) 1.02 (0.59–1.77) 333 55 93 1.28 (0.77–2.14) 0.80 (0.56–1.15) 
    10–14 93 20 25 0.76 (0.38–1.56) 0.98 (0.50–1.92) 344 44 127 1.16 (0.71–1.88) 1.02 (0.75–1.40) 
    ≥15 25 0.71 (0.24–2.16) 1.41 (0.56–3.54) 217 30 79 1.28 (0.76–2.14) 0.90 (0.64–1.26) 
    Trend P    0.42 0.45    0.48 0.81 
    Test for homogeneity of trends P    0.22     0.43  
Time since last use (y) 
    <5 130 26 38 0.68 (0.35–1.32) 0.97 (0.52–1.81) 35 0.69 (0.19–2.45) 0.39 (0.15–0.98) 
    5–9 89 23 34 0.88 (0.44–1.76) 1.35 (0.71–2.55) 27 1.13 (0.36–3.58) 0.50 (0.18–1.38) 
    10–14 153 33 35 0.76 (0.40–1.45) 0.82 (0.44–1.52) 66 12 33 1.42 (0.67–2.98) 1.35 (0.82–2.22) 
    15–19 155 31 33 0.70 (0.37–1.34) 0.78 (0.41–1.46) 172 20 53 0.96 (0.52–1.76) 0.87 (0.58–1.29) 
    ≥20 120 20 35 0.59 (0.29–1.21) 1.10 (0.58–2.08) 658 104 218 1.31 (0.87–2.00) 0.93 (0.70–1.22) 
    Trend P    0.26 0.64    0.17 0.90 
    Test for homogeneity of trends P    0.56     0.19  

NOTE: Triple negative, ER/PR/HER2; luminal A, ER+ or PR+ plus HER2. Adjusted for study site, race, education, age, family history of breast cancer, age at menarche, menopausal status, BMI, and parity.

Among older women, those who had their first full-term pregnancies at or after age 25 years seemed to have a higher risk of luminal A breast cancer than those who had their first full-term pregnancies before age 20 years (Ptrend = 0.04); however, the risk estimates declined in the oldest age group and the CI for the risk estimate for women with a first full-term pregnancy at or after age 30 years included 1.0 (OR, 1.22; 95% CI, 0.71–2.09; Table 4).

Table 4.

Multivariable adjusted OR and 95% CI for triple-negative and luminal A breast cancer associated with reproductive history by age

Younger (ages 35–44 y)Older (ages 45–64 y)
No. controlsNo. triple negativeNo. luminal AOR (95% CI) of triple negativeOR (95% CI) of luminal ANo. controlsNo. triple negativeNo. luminal AOR (95% CI) of triple negativeOR (95% CI) of luminal A
No. full-term pregnancies 
    Never pregnant 70 19 26 Reference Reference 106 57 Reference Reference 
    1 140 24 40 0.62 (0.31–1.23) 0.81 (0.45–1.45) 174 31 69 1.77 (0.80–3.91) 0.80 (0.52–1.25) 
    2 219 50 64 0.89 (0.48–1.64) 0.84 (0.49–1.45) 355 56 123 1.70 (0.81–3.58) 0.68 (0.46–1.01) 
    3 127 29 30 0.89 (0.45–1.74) 0.67 (0.36–1.25) 264 27 85 1.15 (0.51–2.55) 0.66 (0.43–1.00) 
    ≥4 76 16 15 0.76 (0.35–1.67) 0.56 (0.26–1.17) 326 47 89 1.48 (0.68–3.21) 0.56 (0.36–0.86) 
    Trend P    0.87 0.09    0.77 0.006 
    Test for homogeneity of trends P 0.16     0.15  
    Only non–full-term pregnancy 89 16 22 0.62 (0.29–1.30) 0.66 (0.34–1.27) 69 11 25 1.61 (0.63–4.13) 0.67 (0.38–1.19) 
Age at first full-term pregnancy* (y) 
    ≤19 163 31 33 Reference Reference 420 72 106 Reference Reference 
    20–24 154 39 51 1.40 (0.80–2.43) 1.61 (0.96–2.69) 460 52 144 0.73 (0.48–1.11) 1.10 (0.81–1.51) 
    25–29 129 25 41 1.14 (0.59–2.20) 1.50 (0.84–2.68) 150 20 83 0.91 (0.50–1.65) 1.95 (1.31–2.90) 
    ≥30 116 24 24 1.43 (0.66–3.09) 0.92 (0.45–1.90) 89 17 33 1.41 (0.71–2.80) 1.22 (0.71–2.09) 
    Trend P    0.48 0.95    0.66 0.04 
    Test for homogeneity of trends P 0.58     0.35  
Duration of breast-feeding* (mo) 
    Never 180 46 60 Reference Reference 532 85 180 Reference Reference 
    <1 61 14 14 0.83 (0.41–1.67) 0.66 (0.34–1.31) 141 24 51 1.11 (0.67–1.84) 1.04 (0.71–1.52) 
    1–6 144 28 36 0.63 (0.36–1.11) 0.61 (0.37–1.02) 190 26 56 0.86 (0.53–1.41) 0.73 (0.51–1.04) 
    7–23 123 20 31 0.45 (0.24–0.87) 0.60 (0.34–1.05) 179 16 60 0.60 (0.34–1.07) 0.86 (0.60–1.23) 
    ≥24 54 11 0.55 (0.24–1.28) 0.35 (0.15–0.86) 77 10 19 0.82 (0.39–1.72) 0.69 (0.40–1.21) 
    Trend P    0.02 0.01    0.14 0.09 
    Test for homogeneity of trends P 0.97     0.80  
Younger (ages 35–44 y)Older (ages 45–64 y)
No. controlsNo. triple negativeNo. luminal AOR (95% CI) of triple negativeOR (95% CI) of luminal ANo. controlsNo. triple negativeNo. luminal AOR (95% CI) of triple negativeOR (95% CI) of luminal A
No. full-term pregnancies 
    Never pregnant 70 19 26 Reference Reference 106 57 Reference Reference 
    1 140 24 40 0.62 (0.31–1.23) 0.81 (0.45–1.45) 174 31 69 1.77 (0.80–3.91) 0.80 (0.52–1.25) 
    2 219 50 64 0.89 (0.48–1.64) 0.84 (0.49–1.45) 355 56 123 1.70 (0.81–3.58) 0.68 (0.46–1.01) 
    3 127 29 30 0.89 (0.45–1.74) 0.67 (0.36–1.25) 264 27 85 1.15 (0.51–2.55) 0.66 (0.43–1.00) 
    ≥4 76 16 15 0.76 (0.35–1.67) 0.56 (0.26–1.17) 326 47 89 1.48 (0.68–3.21) 0.56 (0.36–0.86) 
    Trend P    0.87 0.09    0.77 0.006 
    Test for homogeneity of trends P 0.16     0.15  
    Only non–full-term pregnancy 89 16 22 0.62 (0.29–1.30) 0.66 (0.34–1.27) 69 11 25 1.61 (0.63–4.13) 0.67 (0.38–1.19) 
Age at first full-term pregnancy* (y) 
    ≤19 163 31 33 Reference Reference 420 72 106 Reference Reference 
    20–24 154 39 51 1.40 (0.80–2.43) 1.61 (0.96–2.69) 460 52 144 0.73 (0.48–1.11) 1.10 (0.81–1.51) 
    25–29 129 25 41 1.14 (0.59–2.20) 1.50 (0.84–2.68) 150 20 83 0.91 (0.50–1.65) 1.95 (1.31–2.90) 
    ≥30 116 24 24 1.43 (0.66–3.09) 0.92 (0.45–1.90) 89 17 33 1.41 (0.71–2.80) 1.22 (0.71–2.09) 
    Trend P    0.48 0.95    0.66 0.04 
    Test for homogeneity of trends P 0.58     0.35  
Duration of breast-feeding* (mo) 
    Never 180 46 60 Reference Reference 532 85 180 Reference Reference 
    <1 61 14 14 0.83 (0.41–1.67) 0.66 (0.34–1.31) 141 24 51 1.11 (0.67–1.84) 1.04 (0.71–1.52) 
    1–6 144 28 36 0.63 (0.36–1.11) 0.61 (0.37–1.02) 190 26 56 0.86 (0.53–1.41) 0.73 (0.51–1.04) 
    7–23 123 20 31 0.45 (0.24–0.87) 0.60 (0.34–1.05) 179 16 60 0.60 (0.34–1.07) 0.86 (0.60–1.23) 
    ≥24 54 11 0.55 (0.24–1.28) 0.35 (0.15–0.86) 77 10 19 0.82 (0.39–1.72) 0.69 (0.40–1.21) 
    Trend P    0.02 0.01    0.14 0.09 
    Test for homogeneity of trends P 0.97     0.80  

NOTE: Triple negative, ER/PR/HER2; luminal A, ER+ or PR+ plus HER2. Adjusted for study site, race, education, age, family history of breast cancer, age at menarche, menopausal status, and BMI.

*Also adjusted for parity and mutually adjusted for age at first full-term pregnancy and duration of breast-feeding among parous women.

Similar to the analyses across all age groups, risk of luminal A cancers decreased with an increasing number of full-term pregnancies for both younger and older women (Ptrend = 0.09 and Ptrend = 0.006, respectively; Table 4). Increasing duration of breast-feeding was inversely associated with risk for both subtypes in younger and older women.

Associations with triple-negative and luminal A subtype by p53

We evaluated whether any associations between OC use or reproductive factors and breast cancer risk differed by p53 status alone and did not observe any statistically significant differences in these associations (results not shown). Subclassification of the triple-negative and luminal A subtypes by p53 status did not further differentiate the associations of these subtypes with OC use (Table 5) or reproductive history (Table 6). Although we found that number of full-term pregnancies was statistically significantly associated with luminal A tumors without p53 overexpression (Ptrend = 0.002) and that duration of breast-feeding was statistically significantly associated with both triple-negative (Ptrend = 0.03) and luminal A tumors (Ptrend = 0.008) without p53 overexpression, these associations did not differ statistically from those for the corresponding subtypes where p53 was overexpressed (all homogeneity tests P > 0.20; Table 6).

Table 5.

Multivariable adjusted OR and 95% CI for triple-negative and luminal A breast cancer associated with OCs by p53 status

No. controlsNo. casesOR (95% CI)
Triple negative/p53+Triple negative/p53Luminal A/p53+Luminal A/p53Triple negative/p53+Triple negative/p53Luminal A/p53+Luminal A/p53
OC use 
    Never use 410 26 33 21 134 Reference Reference Reference Reference 
    Ever use 1,605 125 151 91 399 0.98 (0.61–1.57) 1.05 (0.69–1.61) 1.18 (0.70–2.01) 0.89 (0.70–1.14) 
    Test for homogeneity P 0.74    
Duration of use (y) 
    <1 358 22 35 17 99 0.78 (0.43–1.44) 1.12 (0.67–1.87) 1.00 (0.50–1.97) 0.99 (0.72–1.35) 
    1–4 540 34 52 40 139 0.79 (0.45–1.39) 1.08 (0.66–1.76) 1.62 (0.89–2.93) 0.96 (0.71–1.29) 
    5–9 396 41 34 16 85 1.33 (0.77–2.29) 0.97 (0.57–1.65) 0.87 (0.43–1.77) 0.77 (0.55–1.06) 
    ≥10 311 28 30 18 76 1.14 (0.64–2.05) 1.02 (0.60–1.76) 1.14 (0.57–2.25) 0.82 (0.59–1.15) 
    Trend P      0.17 0.85 0.92 0.09 
    Test for homogeneity of trends P 0.18    
Age at first use (y) 
    ≥25 399 22 32 22 114 0.91 (0.50–1.64) 1.09 (0.65–1.82) 1.19 (0.63–2.23) 0.87 (0.65–1.17) 
    20–24 569 36 53 40 154 0.86 (0.49–1.51) 1.10 (0.67–1.80) 1.48 (0.81–2.73) 0.97 (0.72–1.31) 
    18–19 332 37 25 15 65 1.33 (0.74–2.40) 0.75 (0.41–1.36) 0.86 (0.41–1.83) 0.78 (0.54–1.14) 
    <18 305 30 41 14 66 1.03 (0.55–1.93) 1.22 (0.69–2.14) 0.89 (0.41–1.96) 0.90 (0.61–1.34) 
    Trend P      0.60 0.81 0.66 0.43 
    Test for homogeneity of trends P 0.77    
Duration between menarche and first use (y) 
    <5 264 25 33 14 48 0.90 (0.46–1.74) 1.13 (0.62–2.07) 0.93 (0.42–2.07) 0.76 (0.49–1.16) 
    5–9 662 60 59 35 153 1.05 (0.62–1.79) 0.91 (0.55–1.49) 0.99 (0.53–1.86) 0.85 (0.63–1.17) 
    10–14 437 25 39 27 125 0.85 (0.47–1.54) 1.12 (0.67–1.85) 1.35 (0.73–2.50) 0.97 (0.72–1.30) 
    ≥15 242 15 20 15 73 1.08 (0.55–2.10) 1.13 (0.63–2.03) 1.34 (0.67–2.69) 0.89 (0.63–1.24) 
    Trend P      0.99 0.75 0.26 0.70 
    Test for homogeneity of trends P 0.65    
Time since last use (y) 
    <5 165 15 14 10 34 1.06 (0.51–2.23) 0.71 (0.35–1.45) 1.17 (0.49–2.78) 0.72 (0.45–1.15) 
    5–9 116 14 13 32 1.39 (0.66–2.96) 0.97 (0.47–2.01) 1.23 (0.48–3.19) 1.09 (0.67–1.76) 
    10–14 219 23 22 59 1.21 (0.63–2.30) 0.92 (0.50–1.69) 0.80 (0.34–1.89) 1.02 (0.69–1.51) 
    15–19 327 21 30 19 67 0.81 (0.43–1.54) 0.96 (0.55–1.67) 1.20 (0.60–2.40) 0.77 (0.54–1.10) 
    ≥20 778 52 72 46 207 0.93 (0.56–1.56) 1.18 (0.75–1.85) 1.24 (0.71–2.18) 0.91 (0.70–1.19) 
    Trend P      0.53 0.31 0.48 0.53 
    Test for homogeneity of trends P      0.46    
No. controlsNo. casesOR (95% CI)
Triple negative/p53+Triple negative/p53Luminal A/p53+Luminal A/p53Triple negative/p53+Triple negative/p53Luminal A/p53+Luminal A/p53
OC use 
    Never use 410 26 33 21 134 Reference Reference Reference Reference 
    Ever use 1,605 125 151 91 399 0.98 (0.61–1.57) 1.05 (0.69–1.61) 1.18 (0.70–2.01) 0.89 (0.70–1.14) 
    Test for homogeneity P 0.74    
Duration of use (y) 
    <1 358 22 35 17 99 0.78 (0.43–1.44) 1.12 (0.67–1.87) 1.00 (0.50–1.97) 0.99 (0.72–1.35) 
    1–4 540 34 52 40 139 0.79 (0.45–1.39) 1.08 (0.66–1.76) 1.62 (0.89–2.93) 0.96 (0.71–1.29) 
    5–9 396 41 34 16 85 1.33 (0.77–2.29) 0.97 (0.57–1.65) 0.87 (0.43–1.77) 0.77 (0.55–1.06) 
    ≥10 311 28 30 18 76 1.14 (0.64–2.05) 1.02 (0.60–1.76) 1.14 (0.57–2.25) 0.82 (0.59–1.15) 
    Trend P      0.17 0.85 0.92 0.09 
    Test for homogeneity of trends P 0.18    
Age at first use (y) 
    ≥25 399 22 32 22 114 0.91 (0.50–1.64) 1.09 (0.65–1.82) 1.19 (0.63–2.23) 0.87 (0.65–1.17) 
    20–24 569 36 53 40 154 0.86 (0.49–1.51) 1.10 (0.67–1.80) 1.48 (0.81–2.73) 0.97 (0.72–1.31) 
    18–19 332 37 25 15 65 1.33 (0.74–2.40) 0.75 (0.41–1.36) 0.86 (0.41–1.83) 0.78 (0.54–1.14) 
    <18 305 30 41 14 66 1.03 (0.55–1.93) 1.22 (0.69–2.14) 0.89 (0.41–1.96) 0.90 (0.61–1.34) 
    Trend P      0.60 0.81 0.66 0.43 
    Test for homogeneity of trends P 0.77    
Duration between menarche and first use (y) 
    <5 264 25 33 14 48 0.90 (0.46–1.74) 1.13 (0.62–2.07) 0.93 (0.42–2.07) 0.76 (0.49–1.16) 
    5–9 662 60 59 35 153 1.05 (0.62–1.79) 0.91 (0.55–1.49) 0.99 (0.53–1.86) 0.85 (0.63–1.17) 
    10–14 437 25 39 27 125 0.85 (0.47–1.54) 1.12 (0.67–1.85) 1.35 (0.73–2.50) 0.97 (0.72–1.30) 
    ≥15 242 15 20 15 73 1.08 (0.55–2.10) 1.13 (0.63–2.03) 1.34 (0.67–2.69) 0.89 (0.63–1.24) 
    Trend P      0.99 0.75 0.26 0.70 
    Test for homogeneity of trends P 0.65    
Time since last use (y) 
    <5 165 15 14 10 34 1.06 (0.51–2.23) 0.71 (0.35–1.45) 1.17 (0.49–2.78) 0.72 (0.45–1.15) 
    5–9 116 14 13 32 1.39 (0.66–2.96) 0.97 (0.47–2.01) 1.23 (0.48–3.19) 1.09 (0.67–1.76) 
    10–14 219 23 22 59 1.21 (0.63–2.30) 0.92 (0.50–1.69) 0.80 (0.34–1.89) 1.02 (0.69–1.51) 
    15–19 327 21 30 19 67 0.81 (0.43–1.54) 0.96 (0.55–1.67) 1.20 (0.60–2.40) 0.77 (0.54–1.10) 
    ≥20 778 52 72 46 207 0.93 (0.56–1.56) 1.18 (0.75–1.85) 1.24 (0.71–2.18) 0.91 (0.70–1.19) 
    Trend P      0.53 0.31 0.48 0.53 
    Test for homogeneity of trends P      0.46    

NOTE: Triple negative, ER/PR/HER2; luminal A, ER+ or PR+ plus HER2. Adjusted for study site, race, education, age, family history of breast cancer, age at menarche, menopausal status, BMI, and parity.

Table 6.

Multivariable adjusted OR and 95% CI for triple-negative and luminal A breast cancer associated with reproductive history by p53 status

No. controlsNo. casesOR (95% CI)
Triple negative/p53+Triple negative/p53Luminal A/p53+Luminal A/p53Triple negative/p53+Triple negative/p53Luminal A/p53+Luminal A/p53
No. full-term pregnancies 
    Never pregnant 176 10 18 14 69 Reference Reference Reference Reference 
    1 314 27 28 17 92 1.33 (0.62–2.83) 0.81 (0.43–1.53) 0.67 (0.32–1.42) 0.84 (0.58–1.22) 
    2 574 48 58 35 152 1.41 (0.69–2.86) 0.97 (0.55–1.71) 0.75 (0.39–1.45) 0.73 (0.52–1.03) 
    3 391 24 32 20 95 1.10 (0.51–2.39) 0.81 (0.44–1.51) 0.67 (0.32–1.39) 0.66 (0.46–0.96) 
    ≥4 402 31 32 16 88 1.36 (0.63–2.95) 0.80 (0.42–1.52) 0.50 (0.23–1.11) 0.57 (0.38–0.84) 
    Trend P      0.79 0.55 0.15 0.002 
    Test for homogeneity of trends P 0.22    
    Only non–full-term pregnancy 158 11 16 10 37 0.99 (0.40–2.40) 0.87 (0.42–1.78) 0.74 (0.31–1.72) 0.64 (0.40–1.02) 
Age at first full-term pregnancy* (y) 
    ≤19 583 54 49 29 110 Reference Reference Reference Reference 
    20–24 614 34 57 32 163 0.68 (0.42–1.09) 1.14 (0.74–1.74) 0.99 (0.57–1.71) 1.24 (0.93–1.66) 
    25–29 279 26 19 18 106 1.17 (0.67–2.05) 0.84 (0.46–1.54) 1.29 (0.65–2.55) 1.81 (1.27–2.57) 
    ≥30 205 16 25 48 0.94 (0.46–1.94) 1.70 (0.90–3.24) 0.86 (0.35–2.15) 1.07 (0.68–1.68) 
    Trend P      0.92 0.31 0.91 0.12 
    Test for homogeneity of trends P 0.83    
Duration of breast-feeding* (mo) 
    Never 712 57 74 39 201 Reference Reference Reference Reference 
    <1 202 18 20 14 51 1.08 (0.61–1.90) 0.98 (0.57–1.66) 1.25 (0.65–2.40) 0.85 (0.60–1.22) 
    1–6 334 27 27 19 73 0.95 (0.57–1.57) 0.68 (0.42–1.11) 0.92 (0.51–1.66) 0.66 (0.48–0.91) 
    7–23 302 20 16 10 81 0.75 (0.43–1.32) 0.44 (0.24–0.79) 0.50 (0.24–1.05) 0.82 (0.60–1.13) 
    ≥24 131 13 21 0.68 (0.30–1.53) 0.91 (0.46–1.78) 0.78 (0.30–2.02) 0.52 (0.31–0.87) 
    Trend P      0.23 0.03 0.13 0.008 
    Test for homogeneity of trends P 0.93    
No. controlsNo. casesOR (95% CI)
Triple negative/p53+Triple negative/p53Luminal A/p53+Luminal A/p53Triple negative/p53+Triple negative/p53Luminal A/p53+Luminal A/p53
No. full-term pregnancies 
    Never pregnant 176 10 18 14 69 Reference Reference Reference Reference 
    1 314 27 28 17 92 1.33 (0.62–2.83) 0.81 (0.43–1.53) 0.67 (0.32–1.42) 0.84 (0.58–1.22) 
    2 574 48 58 35 152 1.41 (0.69–2.86) 0.97 (0.55–1.71) 0.75 (0.39–1.45) 0.73 (0.52–1.03) 
    3 391 24 32 20 95 1.10 (0.51–2.39) 0.81 (0.44–1.51) 0.67 (0.32–1.39) 0.66 (0.46–0.96) 
    ≥4 402 31 32 16 88 1.36 (0.63–2.95) 0.80 (0.42–1.52) 0.50 (0.23–1.11) 0.57 (0.38–0.84) 
    Trend P      0.79 0.55 0.15 0.002 
    Test for homogeneity of trends P 0.22    
    Only non–full-term pregnancy 158 11 16 10 37 0.99 (0.40–2.40) 0.87 (0.42–1.78) 0.74 (0.31–1.72) 0.64 (0.40–1.02) 
Age at first full-term pregnancy* (y) 
    ≤19 583 54 49 29 110 Reference Reference Reference Reference 
    20–24 614 34 57 32 163 0.68 (0.42–1.09) 1.14 (0.74–1.74) 0.99 (0.57–1.71) 1.24 (0.93–1.66) 
    25–29 279 26 19 18 106 1.17 (0.67–2.05) 0.84 (0.46–1.54) 1.29 (0.65–2.55) 1.81 (1.27–2.57) 
    ≥30 205 16 25 48 0.94 (0.46–1.94) 1.70 (0.90–3.24) 0.86 (0.35–2.15) 1.07 (0.68–1.68) 
    Trend P      0.92 0.31 0.91 0.12 
    Test for homogeneity of trends P 0.83    
Duration of breast-feeding* (mo) 
    Never 712 57 74 39 201 Reference Reference Reference Reference 
    <1 202 18 20 14 51 1.08 (0.61–1.90) 0.98 (0.57–1.66) 1.25 (0.65–2.40) 0.85 (0.60–1.22) 
    1–6 334 27 27 19 73 0.95 (0.57–1.57) 0.68 (0.42–1.11) 0.92 (0.51–1.66) 0.66 (0.48–0.91) 
    7–23 302 20 16 10 81 0.75 (0.43–1.32) 0.44 (0.24–0.79) 0.50 (0.24–1.05) 0.82 (0.60–1.13) 
    ≥24 131 13 21 0.68 (0.30–1.53) 0.91 (0.46–1.78) 0.78 (0.30–2.02) 0.52 (0.31–0.87) 
    Trend P      0.23 0.03 0.13 0.008 
    Test for homogeneity of trends P 0.93    

NOTE: Triple negative, ER/PR/HER2; luminal A, ER+ or PR+ plus HER2. Adjusted for study site, race, education, age, family history of breast cancer, age at menarche, menopausal status, and BMI.

*Also adjusted for parity and mutually adjusted for age at first full-term pregnancy and duration of breast-feeding among parous women.

A recent study reported that, among women ages 20 to 45 years, use of OCs for at least 1 year was associated with a 2.5-fold increased risk for triple-negative breast cancer (45); this association was not observed in another population-based case-control study that included women ages 20 to 74 years (16). We previously reported that OC use was not associated with breast cancer risk among participants in the Women's CARE Study (26). In the current analysis, OC use was not associated with any subtype except for a 2.9-fold increase in risk for triple-negative breast cancer among older women (ages 45–64 years) who started OC use before age 18 years. All of these older triple-negative breast cancer patients began OC use before 1971 when most OCs contained high doses of synthetic estrogen. In contrast, exposure to OCs at an early age in older women did not significantly increase the risk of luminal A breast cancer in our data.

The association with OC use at a young age among older women that is restricted to triple-negative breast cancer can be viewed as inconsistent with the hypothesis that hormone-related risk factors act through estrogen mediated by its receptor (46). However, there is evidence that ER+ progenitor cells produce paracrine signals when exposed to estrogen, which cause the proliferation of nearby ER cells (47). Furthermore, the Breast and Prostate Cancer Cohort Consortium showed that two common haplotypes of the 17β-hydroxysteroid dehydrogenase 1 gene are associated with risk of ER but not ER+ breast cancer (48). This gene encodes 17HSD1, which affects the conversion of estrone to estradiol. The increase in risk for triple-negative invasive breast cancer suggests that early high-dose OC initiation may increase tumor aggressiveness.

We previously reported that multiparity and early age at first birth were associated with reduced relative risk of ER+/PR+ but not of ER/PR tumors, whereas duration of breast-feeding was associated with lower relative risk of both receptor-positive and receptor-negative breast cancer among all cases [who had ER/PR status from Surveillance, Epidemiology, and End Results (SEER)] and control participants of the Women's CARE Study (49). Consistent with our previous findings, in the current analysis, we found that parity was inversely associated with risk for luminal subtypes. Age at first full-term pregnancy was positively associated with luminal A tumors among older women (ages 45–64 years). Neither parity nor age at first full-term pregnancy was associated with triple-negative tumors. These findings, and particularly the inverse association of parity with all subtypes except triple-negative breast cancer, suggest that some hormone-related risk factor profiles differ between triple-negative and other breast cancer subtypes. In addition, the lack of heterogeneity in the effect of breast-feeding in our data suggests that there are different pathways involving the association between breast-feeding and the risk of breast cancer, such as paracrine signals produced by ER+ progenitors described previously (47).

Consistent with our findings, a pooled analysis of two population-based case-control studies conducted in Western Washington State found that nulliparity was marginally associated with an increased risk of ER+ breast cancer but was not associated with triple-negative breast cancer, whereas breast-feeding protected against both ER+ and triple-negative subtypes (9). Our results are also consistent with those from a population-based case-control study conducted in Poland, which found that parity was inversely associated with the luminal A subtype but not with the basal-like subtype (triple-negative plus the expression of HER1 and/or cytokeratin 5; ref. 11). Our results are not consistent with those from a population-based case-control study conducted in North Carolina in which parity and early age at first full-term pregnancy were associated with an increased risk of basal-like (ER, PR, HER2, HER1+, and/or cytokeratin 5/6+) breast cancer and long duration of breast-feeding was associated with reduced risk of basal-like but not luminal A breast cancer (16). These inconsistencies could be due to some important differences between the North Carolina study and ours, such as the participants' age distribution (ranges: 20–74 versus 35–64 years), the breast cancer case patients' stage (in situ and invasive versus only invasive), control subjects' participant rates (57% versus 74%), analysis approach (each subtype separately compared with control group using unconditional logistic regression models versus all subtypes simultaneously compared with control group using unconditional polychotomous logistic regression models), and different reference groups when testing the effects of age at first full-term pregnancy and breast-feeding (reference group including nulliparous women versus analysis restricted to parous women).

To our knowledge, this study is the first to examine whether p53 status modifies the association of OC use and reproductive factors with risk of invasive triple-negative or luminal A breast cancer. p53 gene mutations may cause loss of tumor suppressor function and gain of oncogenic activity (21). Approximately 69% of p53 immunohistochemistry–positive cancers have p53 gene mutations (41). Whereas 92% of missense p53 gene mutations are associated with p53 immunohistochemistry positivity, only 45% of p53 nonsense or other gene mutations are associated with immunohistochemistry positivity (41). Because the vast majority of p53 gene mutations are missense mutations, p53 overexpression and p53 gene mutation are highly correlated. We speculated that this would result in a stronger association between hormone-related risk factors and the risk of breast cancer with p53 overexpression because hormones drive cell proliferation and, therefore, increase the probability for the accumulation of random genetic errors (50). However, our data did not show any differences in associations of OC use or reproductive factors when triple-negative tumors and luminal A tumors were further classified by p53 overexpression status. We did observe that the number of full-term pregnancies was statistically significantly associated with luminal A tumors without p53 overexpression and that duration of breast-feeding was statistically significantly associated with both triple-negative and luminal A tumors without p53 overexpression. These findings may have resulted from the larger sample sizes for tumor subtypes lacking p53 overexpression than subtypes that overexpress p53.

Where p53 has previously been examined alone, reproductive factor associations did not differ by p53 status (2224), which is consistent with our results. One previous study showed that longer duration of OC use was more strongly associated with an increase in the risk of p53+ than p53 breast cancer among women at ages 20 to 54 years (24). Another study found that this difference in the association with OC use between p53 and p53+ tumors existed among younger (age <45 years) but not older women (22). In a third study, OC use was not associated with either p53+ or p53 tumors (23).

This study has several limitations. We obtained paraffin-embedded tissue for 80% of the samples requested; however, we did not request tissue for all eligible case patients because of funding constraints. We compared demographic characteristics, family history of breast cancer, aspects of OC use, reproductive factors, tumor size, and tumor stage between our eligible case patients with and without known ER, PR, HER2, and p53 status from the centralized laboratory (results not shown). Case patients with information on these four biomarkers were more likely to have been diagnosed in LA than in Detroit, to have been better educated, and to have had larger tumors than those without this information. Parous case patients with known ER, PR, HER2, and p53 status had, on average, breast-fed 1.4 months longer, but no statistically significant differences were detected for other factors examined. The difference in duration of breast-feeding could lead us to underestimate any protective effect of breast-feeding on overall breast cancer risk in the patients with biomarker results, but it is unlikely that this bias would differ across tumor subtypes. Further, although previous research shows that p53 expression and p53 mutation status determined by fluorescent in situ hybridization analysis are strongly correlated, assessment of p53 expression by immunohistochemistry may misclassify some tumors.

In conclusion, our results support the contention that some hormone-related risk factor profiles differ between triple-negative and other breast cancer subtypes defined by ER, PR, and HER2 status, but no further consistent differences are noted when p53 is also considered.

No potential conflicts of interest were disclosed.

We thank Dr. Karen Petrosyan, Armine Arakelyan, Hasmik Toumaian, and Judith Udove for technical assistance in the performance of the immunohistochemical assays for this study and the collaborators who contributed to the development and conduct of the Women's CARE Study but who did not directly contribute to the current study: Janet Daling, Dennis Deapen, Jonathan Liff, Sandra Norman, and Phyllis Wingo.

Grant Support: National Institute for Child Health and Human Development grant NO1-HD-3-3175 and National Cancer Institute grant CA48780. Data collection for the Women's CARE Study was supported by the National Institute of Child Health and Human Development and National Cancer Institute, NIH, through contracts with Emory University (N01-HD-3-3168), Fred Hutchinson Cancer Research Center (N01-HD-2-3166), Karmanos Cancer Institute at Wayne State University (N01-HD-3-3174), University of Pennsylvania (NO1-HD-3-3276), and University of Southern California (N01-HD-3-3175) and Interagency Agreement with Centers for Disease Control and Prevention (Y01-HD-7022). Collection of cancer incidence data in LA County by University of Southern California was supported by California Department of Health Services as part of statewide cancer reporting program mandated by California Health and Safety Code, Section 103885. Support for use of SEER cancer registries through contracts N01-PC-67006 (Atlanta), N01-CN-65064 (Detroit), N01-PC-67010 (LA), and N01-CN-0532 (Seattle).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1
Althuis
MD
,
Fergenbaum
JH
,
Garcia-Closas
M
,
Brinton
LA
,
Madigan
MP
,
Sherman
ME
. 
Etiology of hormone receptor-defined breast cancer: a systematic review of the literature
.
Cancer Epidemiol Biomarkers Prev
2004
;
13
:
1558
68
.
2
Lord
SJ
,
Bernstein
L
,
Johnson
KA
, et al
. 
Breast cancer risk and hormone receptor status in older women by parity, age of first birth, and breastfeeding: a case-control study
.
Cancer Epidemiol Biomarkers Prev
2008
;
17
:
1723
30
.
3
Ma
H
,
Bernstein
L
,
Pike
MC
,
Ursin
G
. 
Reproductive factors and breast cancer risk according to joint estrogen and progesterone receptor status: a meta-analysis of epidemiological studies
.
Breast Cancer Res
2006
;
8
:
R43
.
4
Kumar-Sinha
C
,
Ignatoski
KW
,
Lippman
ME
,
Ethier
SP
,
Chinnaiyan
AM
. 
Transcriptome analysis of HER2 reveals a molecular connection to fatty acid synthesis
.
Cancer Res
2003
;
63
:
132
9
.
5
Ross
JS
,
Fletcher
JA
,
Linette
GP
, et al
. 
The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy
.
Oncologist
2003
;
8
:
307
25
.
6
Gullick
WJ
,
Love
SB
,
Wright
C
, et al
. 
c-erbB-2 protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes
.
Br J Cancer
1991
;
63
:
434
8
.
7
Ma
H
,
Luo
J
,
Press
MF
,
Wang
Y
,
Bernstein
L
,
Ursin
G
. 
Is there a difference in the association between percent mammographic density and subtypes of breast cancer? Luminal A and triple-negative breast cancer
.
Cancer Epidemiol Biomarkers Prev
2009
;
18
:
479
85
.
8
Press
MF
,
Sauter
G
,
Bernstein
L
, et al
. 
Diagnostic evaluation of HER-2 as a molecular target: an assessment of accuracy and reproducibility of laboratory testing in large, prospective, randomized clinical trials
.
Clin Cancer Res
2005
;
11
:
6598
607
.
9
Phipps
AI
,
Malone
KE
,
Porter
PL
,
Daling
JR
,
Li
CI
. 
Reproductive and hormonal risk factors for postmenopausal luminal, HER-2-overexpressing, and triple-negative breast cancer
.
Cancer
2008
;
113
:
1521
6
.
10
Trivers
KF
,
Lund
MJ
,
Porter
PL
, et al
. 
The epidemiology of triple-negative breast cancer, including race
.
Cancer Causes Control
2009
;
20
:
1071
82
.
11
Yang
XR
,
Sherman
ME
,
Rimm
DL
, et al
. 
Differences in risk factors for breast cancer molecular subtypes in a population-based study
.
Cancer Epidemiol Biomarkers Prev
2007
;
16
:
439
43
.
12
Dent
R
,
Trudeau
M
,
Pritchard
KI
, et al
. 
Triple-negative breast cancer: clinical features and patterns of recurrence
.
Clin Cancer Res
2007
;
13
:
4429
34
.
13
Reis-Filho
JS
,
Tutt
AN
. 
Triple negative tumours: a critical review
.
Histopathology
2008
;
52
:
108
18
.
14
Sorlie
T
,
Tibshirani
R
,
Parker
J
, et al
. 
Repeated observation of breast tumor subtypes in independent gene expression data sets
.
Proc Natl Acad Sci U S A
2003
;
100
:
8418
23
.
15
Sorlie
T
,
Wang
Y
,
Xiao
C
, et al
. 
Distinct molecular mechanisms underlying clinically relevant subtypes of breast cancer: gene expression analyses across three different platforms
.
BMC Genomics
2006
;
7
:
127
.
16
Millikan
RC
,
Newman
B
,
Tse
CK
, et al
. 
Epidemiology of basal-like breast cancer
.
Breast Cancer Res Treat
2008
;
109
:
123
39
.
17
Gasco
M
,
Shami
S
,
Crook
T
. 
The p53 pathway in breast cancer
.
Breast Cancer Res
2002
;
4
:
70
6
.
18
Davidoff
AM
,
Humphrey
PA
,
Iglehart
JD
,
Marks
JR
. 
Genetic basis for p53 overexpression in human breast cancer
.
Proc Natl Acad Sci U S A
1991
;
88
:
5006
10
.
19
Allred
DC
,
Elledge
R
,
Clark
GM
,
Fuqua
SA
. 
The p53 tumor-suppressor gene in human breast cancer
.
Cancer Treat Res
1994
;
71
:
63
77
.
20
Smith
HS
. 
Tumor-suppressor genes in breast cancer progression
.
Cancer Treat Res
1994
;
71
:
79
96
.
21
Greenblatt
MS
,
Bennett
WP
,
Hollstein
M
,
Harris
CC
. 
Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis
.
Cancer Res
1994
;
54
:
4855
78
.
22
Furberg
H
,
Millikan
RC
,
Geradts
J
, et al
. 
Reproductive factors in relation to breast cancer characterized by p53 protein expression (United States)
.
Cancer Causes Control
2003
;
14
:
609
18
.
23
Gammon
MD
,
Hibshoosh
H
,
Terry
MB
, et al
. 
Cigarette smoking and other risk factors in relation to p53 expression in breast cancer among young women
.
Cancer Epidemiol Biomarkers Prev
1999
;
8
:
255
63
.
24
van der Kooy
K
,
Rookus
MA
,
Peterse
HL
,
van Leeuwen
FE
. 
p53 protein overexpression in relation to risk factors for breast cancer
.
Am J Epidemiol
1996
;
144
:
924
33
.
25
Marchbanks
PA
,
McDonald
JA
,
Wilson
HG
, et al
. 
The NICHD Women's Contraceptive and Reproductive Experiences Study: methods and operational results
.
Ann Epidemiol
2002
;
12
:
213
21
.
26
Marchbanks
PA
,
McDonald
JA
,
Wilson
HG
, et al
. 
Oral contraceptives and the risk of breast cancer
.
N Engl J Med
2002
;
346
:
2025
32
.
27
Norman
SA
,
Berlin
JA
,
Weber
AL
, et al
. 
Combined effect of oral contraceptive use and hormone replacement therapy on breast cancer risk in postmenopausal women
.
Cancer Causes Control
2003
;
14
:
933
43
.
28
Bacus
S
,
Flowers
JL
,
Press
MF
,
Bacus
JW
,
McCarty
KS,
 Jr.
The evaluation of estrogen receptor in primary breast carcinoma by computer-assisted image analysis
.
Am J Clin Pathol
1988
;
90
:
233
9
.
29
Greene
GL
,
King
WJ
,
Press
MF
. 
Monoclonal antibodies as probes for estrogen receptor
. In:
Labrie
F
,
Proulx
L
, editors.
Endocrinology
.
Elsevier Publishing
; 
1984
, p.
541
4
.
30
Greene
GL
,
Press
MF
. 
Structure and dynamics of the estrogen receptor
.
J Steroid Biochem
1986
;
24
:
1
7
.
31
Press
MF
,
Greene
GL
. 
An immunocytochemical method for demonstrating estrogen receptor in human uterus using monoclonal antibodies to human estrophilin
.
Lab Invest
1984
;
50
:
480
6
.
32
Press
MF
,
Nousek-Goebl
N
,
King
WJ
,
Herbst
AL
,
Greene
GL
. 
Immunohistochemical assessment of estrogen receptor distribution in the human endometrium throughout the menstrual cycle
.
Lab Invest
1984
;
51
:
495
503
.
33
Greene
GL
,
Press
MF
. 
Immunochemical evaluation of estrogen receptor and progesterone receptor in breast cancer
. In:
Ceriani
RL
, editor.
Immunological approaches to the diagnosis and therapy of breast cancer
.
Plenum Publishing Corp.
; 
1987
, p.
119
35
.
34
Press
MF
,
Greene
GL
. 
Localization of progesterone receptor with monoclonal antibodies to the human progestin receptor
.
Endocrinology
1988
;
122
:
1165
75
.
35
Press
MF
,
Xu
SH
,
Wang
JD
,
Greene
GL
. 
Subcellular distribution of estrogen receptor and progesterone receptor with and without specific ligand
.
Am J Pathol
1989
;
135
:
857
64
.
36
Press
M
,
Spaulding
B
,
Groshen
S
, et al
. 
Comparison of different antibodies for detection of progesterone receptor in breast cancer
.
Steroids
2002
;
67
:
799
813
.
37
Press
MF
. 
Estrogen and progesterone receptors in breast cancer
.
Adv Pathol Lab Med
1993
;
6
:
117
48
.
38
Ma
H
,
Wang
Y
,
Sullivan-Halley
J
, et al
. 
Breast cancer receptor status: do results from a centralized pathology laboratory agree with SEER registry reports?
Cancer Epidemiol Biomarkers Prev
2009
;
18
:
2214
20
.
39
Press
MF
,
Slamon
DJ
,
Flom
KJ
,
Park
J
,
Zhou
J-Y
,
Bernstein
L
. 
Evaluation of HER-2/neu gene amplification and overexpression: comparison of frequently used assay methods in a molecularly characterized cohort of breast cancer specimens
.
J Clin Oncol
2002
;
20
:
3095
105
.
40
Saffari
B
,
Bernstein
L
,
Hong
DC
, et al
. 
Association of p53 mutations and a codon 72 single nucleotide polymorphism with lower overall survival and responsiveness to adjuvant radiotherapy in endometrioid endometrial carcinomas
.
Int J Gynecol Cancer
2005
;
15
:
952
63
.
41
Wen
WH
,
Reles
A
,
Runnebaum
IB
, et al
. 
p53 mutations and expression in ovarian cancers: correlation with overall survival
.
Int J Gynecol Pathol
1999
;
18
:
29
41
.
42
Schmider
A
,
Gee
C
,
Friedmann
W
, et al
. 
p21 (WAF1/CIP1) protein expression is associated with prolonged survival but not with p53 expression in epithelial ovarian carcinoma
.
Gynecol Oncol
2000
;
77
:
237
42
.
43
Simon
MS
,
Korczak
JF
,
Yee
CL
, et al
. 
Breast cancer risk estimates for relatives of white and African American women with breast cancer in the Women's Contraceptive and Reproductive Experiences Study
.
J Clin Oncol
2006
;
24
:
2498
504
.
44
Ursin
G
,
Bernstein
L
,
Wang
Y
, et al
. 
Reproductive factors and risk of breast carcinoma in a study of white and African-American women
.
Cancer
2004
;
101
:
353
62
.
45
Dolle
JM
,
Daling
JR
,
White
E
, et al
. 
Risk factors for triple-negative breast cancer in women under the age of 45 years
.
Cancer Epidemiol Biomarkers Prev
2009
;
18
:
1157
66
.
46
Anderson
E
. 
The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis
.
Breast Cancer Res
2002
;
4
:
197
201
.
47
Dontu
G
,
El-Ashry
D
,
Wicha
MS
. 
Breast cancer, stem/progenitor cells and the estrogen receptor
.
Trends Endocrinol Metabol
2004
;
15
:
193
7
.
48
Feigelson
HS
,
Cox
DG
,
Cann
HM
, et al
. 
Haplotype analysis of the HSD17B1 gene and risk of breast cancer: a comprehensive approach to multicenter analyses of prospective cohort studies
.
Cancer Res
2006
;
66
:
2468
75
.
49
Ursin
G
,
Bernstein
L
,
Lord
SJ
, et al
. 
Reproductive factors and subtypes of breast cancer defined by hormone receptor and histology
.
Br J Cancer
2005
;
93
:
364
71
.
50
Henderson
BE
,
Feigelson
HS
. 
Hormonal carcinogenesis
.
Carcinogenesis
2000
;
21
:
427
33
.

Supplementary data