Implication des bisphénols dans la régulation et la tumorigenèse des cellules souches mammaires via une interaction entre les signalisations ERalpha36 et BMP2

Stem cells are regulated by several cues from their microenvironment and it is becoming increasingly clear that perturbations of these signals can participate to transformation. Previously, our lab showed that BMP2 (B2) was able to induce the transformation of breast epithelial stem cells and it was overproduced in luminal breast cancer microenvironment. It was also found that a potential source of this B2 over-expression was the exposure to oestrogen (E2)-mimetic environmental pollutants such as BPA, which is also involved in breast cancer development due to its effect on oestrogen receptor ERα66. Several studies have already reported the dangerous effects of BPA on human health, leading to its replacement by other bisphenols, such as BPS and BPF, showing a lower ERα66 affinity. However, some studies suggest that these BPA’s alternatives could also be endocrine disruptors via ERα36 activation, an ERα66 isoform, calling into question their innocuity and the audit criteria used to evaluate their effect on human health. All these data leading us to postulate the hypothesis of bisphenols involvement in stem cells properties dysregulation and transformation, through the cooperation between BMP2 signalling and ERα36. We had followed the effect of a chronical exposure to E2, BPA, BPS, BPF, alone or in combination with B2, in the ERα66-/ ERα46-/ ERα36+ immature human mammary epithelial cell line’s activity and transformation. We found that chronical exposure to BPS or BPF act in collaboration with B2 in favour to a stem cell compartment enrichment. One molecular mechanism could be probably due to B2 hypersensitivity induction, leading to potentiation of its canonical pathway. Moreover, we also identify for the first time, the existence of a physical interaction between ERα36 and two major actors of B2 pathway: BMPR1B and SMAD1. Furthermore, we highlight that ERα36/BMPR1B interaction is lose after chronical exposure to bisphenols or E2, with B2 as well as without, suggesting existence of a crosstalk between ERα36 and B2 signalling pathway. This work allowed to better understand relation existing between ERα36 and B2 pathway, two important pathways independently involved in breast cancers development. Linking these two signalling allows to better understand how hormonal signals, endogen or from our environment, participate altogether to modify physiological cell regulation. In addition to its fundamental significance, this work strongly emphasizes the necessity to