Background: Elevated body mass index (BMI) is associated with increased risk of postmenopausal breast cancer, which may be partly attributable to an inflammation-aromatase axis. Most individuals with elevated BMI harbor white adipose tissue inflammation (WATi), defined by the presence of crown-like structures in the breast (CLS-B). CLS-B are composed of a dead/dying adipocyte surrounded by CD68+ macrophages. This inflammation is associated with activation of NF-κB and elevated expression of aromatase, which could contribute to tumor development. Additionally, WATi correlates with several circulating changes, including hyperinsulinemia, which increase breast cancer risk. Although breast WATi correlates with rising BMI, it is also present in some normal BMI individuals. Beyond inherited germline syndromes, the etiology of breast cancer in individuals with normal BMI is not well understood. Here we examined the impact of breast WATi on breast aromatase expression and circulating factors in women with normal BMI.

Methods: Non-tumorous breast tissue and fasting blood were collected from 72 women with BMI < 25 kg/m2 undergoing mastectomy at MSKCC. Breast inflammation was detected by the presence of CLS-B using CD68 immunohistochemistry. The primary objective was to determine if breast WATi in normal BMI individuals correlates with elevated aromatase levels in the breast, measured by qPCR, western blotting, immunofluorescence and enzyme activity. Secondary objectives included assessment of breast adipocyte size and circulating metabolic and inflammatory factors.

Results: Breast inflammation was present in 39% of women. Median BMI was 23.0 (range 18.4 to 24.9) in women with breast WATi versus 21.8 (range 17.3 to 24.6) in those without inflammation (P=0.04). Aromatase mRNA expression was positively correlated with WATi (CLS-B/cm2; P=0.002). Those with severe WATi had highest aromatase mRNA levels, compared to those with no or mild WATi (P=0.005). Aromatase protein, assessed by measuring adipose stromal cell-specific immunofluorescence or western blotting, and activity were also higher in CLS-B+ cases compared to CLS-B- (P<0.001). Breast WATi correlated with larger adipocytes (P=0.01) and higher circulating levels of C-reactive protein, leptin, insulin, and triglycerides (P<0.05). Insulin resistance, characterized by the homeostasis model (HOMA2-IR), correlated with breast WATi (P=0.004). Finally, leptin, a known inducer of aromatase and driver of cancer growth, correlated with higher breast aromatase levels (P=0.02) and larger adipocytes (P<0.01).

Conclusions: A metabolically unhealthy state occurs in women with inflamed breast adipose despite having a normal BMI. This subclinical inflammatory state is characterized by elevated aromatase in the breast, insulin resistance, and dysplipidemia. The presence of enlarged adipocytes in the breasts of normal BMI women with inflammation suggests a state of hyperadiposity which could not be predicted based on BMI alone. These findings indicate that normal BMI metabolic obesity may be associated with increased cancer risk. Our results suggest that objective measurements of adiposity rather than BMI may help to identify individuals at increased risk for disease.

Citation Format: Iyengar NM, Brown KA, Zhou XK, Subbaramaiah K, Giri DD, Gucalp A, Howe LR, Zahid H, Bhardwaj P, Wendel NK, Falcone DJ, Morrow M, Wang H, Williams S, Pollak M, Hudis CA, Dannenberg AJ. Metabolic obesity, adipose inflammation and aromatase: Potential drivers of breast cancer risk in women with normal body mass index [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD5-05.