Long-term exposure to bisphenol A or benzo(a)pyrene alters the fate of human mammary epithelial stem cells in response to BMP2 and BMP4, by pre-activating BMP signaling

Abstract

Bone morphogenetic protein 2 (BMP2) and BMP4 are key regulators of the fate and differentiation of human mammary epithelial stem cells (SCs), as well as of their niches, and are involved in breast cancer development. We established that MCF10A immature mammary epithelial cells reliably reproduce the BMP response that we previously identified in human primary epithelial SCs. In this model, we observed that BMP2 promotes luminal progenitor commitment and expansion, whereas BMP4 prevents lineage differentiation. Environmental pollutants are known to promote cancer development, possibly by providing cells with stem-like features and by modifying their niches. Bisphenols, in particular, were shown to increase the risk of developing breast cancer. Here, we demonstrate that chronic exposure to low doses of bisphenol A (BPA) or benzo(a)pyrene (B(a)P) alone has little effect on SCs properties of MCF10A cells. Conversely, we show that this exposure affects the response of immature epithelial cells to BMP2 and BMP4. Furthermore, the modifications triggered in MCF10A cells on exposure to pollutants appeared to be predominantly mediated by altering the expression and localization of type-1 receptors and by pre-activating BMP signaling, through the phosphorylation of small mothers against decapentaplegic 1/5/8 (SMAD1/5/8). By analyzing stem and progenitor properties, we reveal that BPA prevents the maintenance of SC features prompted by BMP4, whereas promoting cell differentiation towards a myoepithelial phenotype. Inversely, B(a)P prevents BMP2-mediated luminal progenitor commitment and expansion, leading to the retention of stem-like properties. Overall, our data indicate that BPA and B(a)P distinctly alter the fate and differentiation potential of mammary epithelial SCs by modulating BMP signaling.

HDAC7‐mediated control of tumour microenvironment maintains proliferative and stemness competence of human mammary epithelial cells

“…The behaviour of stem cells can be influenced by different environmental factors (Shaw et al ., ). Particularly, previous studies have shown that BMP4 can increase the number of mammospheres generated by MCF10A cells (Clément et al ., ). When both HDAC7 +/+ and HDAC7 −/− cells were treated with BMP4, the number of spheres was augmented.…”

“…A,B). The combination of the surface markers CD44 + /CD24 low was used to distinguish stem‐like cells (Amin et al ., ; Clément et al ., ; Shaw et al ., ). We did not observe such a reduction of this population in HDAC7 −/− cells, to justify the failure in the mammosphere assay (Fig.…”

“…Since a recent study claimed a role of HDAC7 in breast cancer stem cells (Witt et al ., ), we compared sphere generation by HDAC7 −/− and HDAC7 +/+ cells. As previously reported (Amin et al ., ; Clément et al ., ; Qu et al ., ), MCF10A can form spheres with low efficiency (Fig. A).…”

“…MCF10A cells can form spheres with low efficiency when grown in suspension (Amin et al, 2016;Cl ement et al, 2017;Qu et al, 2015). This in vitro assay is commonly used to measure the presence of rare stem-/ progenitor-like cells (Shaw et al, 2012).…”

Blocking TGF-β and BMP SMAD-dependent cell differentiation is a master key to expand all kinds of epithelial stem cells

“…Indeed, chronic long-term exposure to high levels of soluble BMP2 could initiate the luminal transformation of predisposed breast epithelial stem cells through binding to BMPR1b (5). In addition, environmental pollutants such as estrogeno-mimetic bisphenols, are able to initiate deregulations of the BMP signaling by altering BMP pathway members expression within epithelial stem cells, as well as BMP expression itself by their microenvironment (5,17). In this context, it is interesting to observe an absence of induced tumorigenesis after long-term dual TGF-β and BMP pathways inhibition in primary epithelial stem cells.…”