In Utero Exposure to Bisphenol a Promotes Mammary Tumor Risk in MMTV-Erbb2 Transgenic Mice Through the Induction of ER-erbB2 Crosstalk

Abstract

Bisphenol A (BPA) is the most common environmental endocrine disrupting chemical. Studies suggest a link between perinatal BPA exposure and increased breast cancer risk, but the underlying mechanisms remain unclear. This study aims to investigate the effects of in utero BPA exposure on mammary tumorigenesis in MMTV-erbB2 transgenic mice. Pregnant mice were subcutaneously injected with BPA (0, 50, 500 ng/kg and 250 µg/kg BW) daily between gestational days 11–19. Female offspring were examined for mammary tumorigenesis, puberty onset, mammary morphogenesis, and signaling in ER and erbB2 pathways. In utero exposure to low dose BPA (500 ng/kg) induced mammary tumorigenesis, earlier puberty onset, increased terminal end buds, and prolonged estrus phase, which was accompanied by proliferative mammary morphogenesis. CD24/49f-based FACS analysis showed that in utero exposure to 500 ng/kg BPA induced expansion of luminal and basal/myoepithelial cell subpopulations at PND 35. Molecular analysis of mammary tissues at PND 70 showed that in utero exposure to low doses of BPA induced upregulation of ERα, p-ERα, cyclin D1, and c-myc, concurrent activation of erbB2, EGFR, erbB-3, Erk1/2, and Akt, and upregulation of growth factors/ligands. Our results demonstrate that in utero exposure to low dose BPA promotes mammary tumorigenesis in MMTV-erbB2 mice through induction of ER-erbB2 crosstalk and mammary epithelial reprogramming, which advance our understanding of the mechanism associated with in utero exposure to BPA-induced breast cancer risk. The studies also support using MMTV-erbB2 mouse model for relevant studies.

Different bisphenols induce non-monotonous changes in miRNA expression and LINE-1 methylation in two cell lines

“…Various studies confirm changes in the expression of these genes or proteins upon bisphenol exposure: in breast cancer cell lines, low concentrations of BPAF [ 61 ] and tetrachloro-BPA [ 62 ] enhanced protein expression of c-Myc and cyclin D1, important for cell cycle progression. In mice, this led to an activation of epidermal growth factor receptor (EGFR) and subsequent increases in growth factor expression related to mammary carcinoma [ 63 ]. EGFR, linked to the erythroblastic leukemia viral oncogene signaling pathway, is the receptor for epidermal growth factor and TGF-α, among others, and thus stimulates cell growth while inhibiting apoptosis, which is why it is also considered as an oncogene [ 64 ].…”

A Folate- and Vitamin B12-Deficient Diet Decreases the Latency and Increases the Incidence of Mammary Tumors in MMTV-ErbB2 Transgenic Mice

“…The current data indicated that FVD-induced HHcy signi cantly activated ErbB2/MAPK/PI3K/Akt and ERα pathways. Since ErbB2-ER signaling crosstalk has widely reported to promote mammary tumor development [27,56] , it was suggested that ErbB2-ER signaling crosstalk may participate in FVD-induced HHcy mediated tumor development in MMTV-ErbB2 mice. These results suggested the ErbB2-ER signaling activation was due to FVD administration, and was not speci c to MMTV-ErbB2 activation in MMTV-ErbB2 mice.…”

How microplastic components influence the immune system and impact on children health: Focus on cancer

“…In order to understand the mechanisms involved in this modulation, another group performed experiments using mice and evaluating the in utero exposure of this compound (Potischman & Troisi, 1999). BPA modulated the protein expression of classical targets of the ER pathway such as cyclin D1, c-myc, and Bcl-2; moreover, the concurrent activation of erbB2, EGFR, erbB-3, Erk1/2, and Akt, and the upregulation of their respective growth factors/ligands was also reported (Ma et al, 2020). It is known that the proliferation of breast tissue is governed by both the ERs and their natural ligands and that females have higher levels of them compared to males.…”