Estradiol/GPER affects the integrity of mammary duct-like structures in vitro

Abstract

High estrogen concentration leads to an inflammatory reaction in the mammary gland tissue in vivo;however, the detailed mechanism underlying its specific effects on the breast duct has not been fully clarified. We used 3D-cultured MCF-10A acini as a breast duct model and demonstrated various deleterious effects of 17-β estradiol (E2), including the destruction of the basement membrane surrounding the acini, abnormal adhesion between cells, and cell death via apoptosis and pyroptosis. Moreover, we clarified the mechanism underlying these phenomena: E2 binds to GPER in MCF-10A cells and stimulates matrix metalloproteinase 3 (MMP-3) and interleukin-1β (IL-1β) secretion via JNK and p38 MAPK signaling pathways. IL-1β activates the IL-1R1 signaling pathway and induces continuous MMP-3 and IL-1β secretion. Collectively, our novel findings reveal an important molecular mechanism underlying the effects of E2 on the integrity of duct-like structures in vitro. Thus, E2 may act as a trigger for ductal carcinoma transition in situ.Estrogens are female hormones secreted mainly by ovaries. They serve diverse functions in the female reproductive organs (e.g., uterus and mammary gland) as well as bones, blood vessels, nerves, and brain 1-4 . Estrogens comprise three types: estrone (E1), 17-β estradiol (E2), and estriol (E3) 5 . E2 binds to estrogen receptors α and β, and the complex formed migrates to DNA of the target gene to activate its transcription 6 . In addition to these classic transcriptional mechanisms, G-protein-coupled receptor 30 (GPER) is an estrogen receptor involved in nongenomic mechanisms 7,8 . GPER expression is tissue-specific, with high expression found in the reproductive system, heart, intestine, ovary, CNS, pancreatic islets, adipose tissue, and neurons. And abnormal GPER expression is associated with depression, hypertension, diabetes, and osteoporosis 9-11 . Also, high GPER expression in breast cancer is associated with increased recurrence 12,13 . Estrogen action via GPER leads to enhanced fibronectin matrix assembly in breast cancer cells 14 . An important biological consequence of GPER activation is the regulation of cell growth and apoptotic cell death 15,16 . In this process, E2 binding to GPER causes G-protein complex dissociation 17,18 , and then the βγ subunit activates the tyrosine kinase Src, which leads to the activation of MAPK pathway 17,18 . GPER activation further activates the downstream signaling molecules such as MAPK and PI3K/ AKT 19,20 .In this study, 3D cultured MCF-10A acini were exposed to E2, which led to the disruption of basement membrane and cell death of some ductal cells. And we further revealed the underlying mechanism in which E2 binding to GPER resulted in cAMP-mediated activation of c-jun N-terminal kinase (JNK) and p38 MAPK signaling pathway, followed by interleukin 1β (IL-1β) and matrix metalloproteinase-3 (MMP-3) expression and secretion. Results Estradiol induces basement membrane disruption in MCF-10A acini.We constructed a 3D model using the immortalized non-transfo...

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Estrogen-Receptor-Positive Breast Cancer in Postmenopausal Women: The Role of Body Composition and Physical Exercise

“…A comprehensive clarification about the role of ERβ in BC is hampered by the presence of five different isoforms of ERβ (ERβ, β2, β3, β4, and β5). However, although more investigations are needed, the general consensus is its suppressor role in BC, since it is able to reduce growth, proliferation and cancer cell migration and invasion mediated by ERα, [ 14 , 22 , 23 , 24 ]. Besides its genomic actions, ER mediates non-genomic effects towards the transmembrane protein, GPER, commonly accepted as being responsible for the extra-nuclear, non-genomic effects of estrogens [ 14 , 25 ].…”