Estrogen Enhances the Cell Viability and Motility of Breast Cancer Cells through the ER?-?Np63-Integrin ?4 Signaling Pathway.

ABSTRACT: Estrogen induces ER?-positive breast cancer aggressiveness via the promotion of cell proliferation and survival, the epithelial-mesenchymal transition, and stem-like properties. Integrin ?4 signaling has been implicated in estrogen/ER?-induced tumorigenicity and anti-apoptosis; however, this signaling cascade poorly understood. ?Np63, an N-terminally truncated isoform of the p63 transcription factor, functions as a transcription factor of integrin?4 and therefore regulates cellular adhesion and survival. Therefore, the aim of the present study was to investigate the estrogen-induced interaction between ER?, ?Np63 and integrin ?4 in breast cancer cells. In ER?-positive MCF-7 cells, estrogen activated ER? transcription, which induced ?Np63 expression. And ?Np63 subsequently induced integrin ?4 expression, which resulted in AKT phosphorylation and enhanced cell viability and motility. Conversely, there was no inductive effect of estrogen on ?Np63-integrin?4-AKT signaling or on cell viability and motility in ER?-negative MDA-MB-231 cells. ?Np63 knockdown abolishes these estrogen-induced effects and reduces cell viability and motility in MCF-7 cells. Nevertheless, ?Np63 knockdown also inhibited cell migration in MDA-MB-231 cells through reducing integrin ?4 expression and AKT phosphorylation. In conclusion, estrogen enhances ER?-positive breast cancer cell viability and motility through activating the ER?-?Np63-integrin ?4 signaling pathway to induce AKT phosphorylated activation. Those findings should be useful to elucidate the crosstalk between estrogen/ER signaling and ?Np63 signaling and provide novel insights into the effects of estrogen on breast cancer progression.

SUBMITTER: Ho JY 

PROVIDER: S-EPMC4742232 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature