Abstract
Full term pregnancy at an early age is the only factor known to consistently protect against breast cancer. Because hormone receptor positive progenitors in the human breast relay endocrine signaling, we here sought to determine whether an experimental mimicry of the third trimester surge of hormones would change their susceptibility to growth stimulation. Hormone receptor positive, reduction mammoplasty-derived human breast epithelial progenitors were exposed to a short-term, pregnancy-level of estradiol, and their subsequent response to estradiol stimulation was analyzed. Exposure to pregnancy-level of estradiol results in subsequent lower sensitivity to estrogen-induced proliferation. Expression array and immunoblotting reveal upregulation of S100A7 and down-regulation of p27, both associated with parity and epithelial differentiation. Notably, we find that the epithelial differentiation is accompanied by upregulation of E-cadherin and down-regulation of vimentin as well as by diminished migration and more mature luminal epithelial differentiation in a mouse transplantation model. Our findings are in support of a de-sensitization mechanism for pregnancy-induced prevention against breast cancer.
Highlights
Full term pregnancy at an early age is the only factor known to consistently protect against breast cancer
We found an increase of E-cadherin along with a decrease in vimentin, c-kit/CD117, and p27 (Fig. 1E and Supplementary Fig. 1), and regulation took place in both culture conditions tested, that is upon E2hi priming in TGFβR2i without epidermal growth factor (EGF) or in TGFβR2i-1 with charcoal-stripped fetal calf serum (CCS)
Since estrogen is a known driver of breast carcinogenesis, such reduction in estrogen sensitivity is likely to be relevant for cancer prevention, but has been difficult to test experimentally because of lack of models of normal-derived E Rpos cells
Summary
Full term pregnancy at an early age is the only factor known to consistently protect against breast cancer. Reduction mammoplasty-derived human breast epithelial progenitors were exposed to a short-term, pregnancy-level of estradiol, and their subsequent response to estradiol stimulation was analyzed. Previous work did not address the role of pregnancy levels of E2 on ERpos cells or whether such levels elicit any long-lasting changes In theory, it could go both ways—either the cells become more transformed or less responsive to estrogens, the latter leading to a reduction in the life-long number of cell divisions, and in turn to a reduced risk of developing breast cancer. We here employ a recently established normal breast luminal ERpos epithelial cell line[6] to explore the effect of a hormonal mimicry of pregnancy and describe its influence on estrogen sensitivity and cell differentiation
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