In utero exposure to estradiol reduces mRNA expression of ERα, BRCA1 and p53 in the postnatal rat mammary gland Free

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Some breast cancers might be pre-initiated already in utero by an exposure to elevated maternal estrogenic environment during pregnancy. Our previous studies have shown that mammary glands of female rats exposed to estradiol during fetal period contain more targets for malignant transformation and exhibit increased susceptibility to carcinogen-induced mammary tumorigenesis. We investigated, using real time PCR, whether in utero exposure to 10 μg estradiol daily between gestation days 10 and 20 causes long-lasting changes in the expression of estrogen regulated genes in the epithelial and/or stromal compartment of the 2- and 3-week-old rat mammary gland. In utero exposure to estradiol reduced the mRNA expression of p53 (p<0.005) and estrogen receptor (ER)-α (p<0.038) in the epithelium (but not in the stroma) of 3-week-old rats, when compared with vehicle-exposed controls. A similar change was seen for BRCA1, but the effect failed to reach statistical significance. No changes between the estradiol and control group were seen on postnatal week 2. The level of expression in the stroma (but not in the epithelium) changed from postnatal week 2 to week 3: ER-α (p<0.011), p53 (p<0.016) and BRCA1 (p<0.034) mRNAs were lower in both the control and in utero estradiol exposed groups on week 3 than on week 2. Thus, compared to the epithelium, the stromal expression of p53 (p<0.026) and BRCA1 (p<0.016) were lower on postnatal week 3, but not on postnatal week 2. ER-α expression in the stroma was significantly higher on week 2, but lower on week 3 (p<0.007). These findings indicate that earlier during postnatal development the expression of ER-α, p53 and BRCA1 is similar in the epithelial and stromal compartments, but on postnatal week 3 their expression shifts predominantly to the epithelium. Further, our data suggest that the increase in mammary tumorigenesis in rats exposed to estradiol in utero is associated with a reduction in the epithelial expression of ER-α, BRCA1 and p53. This, in turn, might lead to a reduced ability to repair DNA damage, which could increase the susceptibility to initiation of breast cancer.