Abstract
Estrogen induces ERα-positive breast cancer aggressiveness via the promotion of cell proliferation and survival, the epithelial-mesenchymal transition, and stem-like properties. Integrin β4 signaling has been implicated in estrogen/ERα-induced tumorigenicity and anti-apoptosis; however, this signaling cascade poorly understood. ΔNp63, an N-terminally truncated isoform of the p63 transcription factor, functions as a transcription factor of integrinβ4 and therefore regulates cellular adhesion and survival. Therefore, the aim of the present study was to investigate the estrogen-induced interaction between ERα, ΔNp63 and integrin β4 in breast cancer cells. In ERα-positive MCF-7 cells, estrogen activated ERα transcription, which induced ΔNp63 expression. And ΔNp63 subsequently induced integrin β4 expression, which resulted in AKT phosphorylation and enhanced cell viability and motility. Conversely, there was no inductive effect of estrogen on ΔNp63-integrinβ4-AKT signaling or on cell viability and motility in ERα-negative MDA-MB-231 cells. ΔNp63 knockdown abolishes these estrogen-induced effects and reduces cell viability and motility in MCF-7 cells. Nevertheless, ΔNp63 knockdown also inhibited cell migration in MDA-MB-231 cells through reducing integrin β4 expression and AKT phosphorylation. In conclusion, estrogen enhances ERα-positive breast cancer cell viability and motility through activating the ERα-ΔNp63-integrin β4 signaling pathway to induce AKT phosphorylated activation. Those findings should be useful to elucidate the crosstalk between estrogen/ER signaling and ΔNp63 signaling and provide novel insights into the effects of estrogen on breast cancer progression.
Highlights
Overexpression of the estrogen receptor alpha (ERα) is observed in approximately 70% of all breast cancer patients, and most breast cancer patients initially respond to anti-estrogen therapy
20% to 40% of patients with breast cancer eventually relapse in distant organs, which remain undetectable for years after primary tumor diagnosis, and this phenomenon is commonly observed in ERα-positive breast cancer
MCF-7 (ERα-positive) and MDA-MB-231 (ERα-negative) breast cancer cell lines were purchased from the Bioresource Collection and Research Center and maintained in Dulbecco’s Modified Eagle Medium (DMEM) containing 10% fetal bovine serum (FBS) at 37°C in a5% CO2 atmosphere
Summary
Overexpression of the estrogen receptor alpha (ERα) is observed in approximately 70% of all breast cancer patients, and most breast cancer patients initially respond to anti-estrogen therapy. 20% to 40% of patients with breast cancer eventually relapse in distant organs (i.e., metastasis), which remain undetectable for years after primary tumor diagnosis, and this phenomenon is commonly observed in ERα-positive breast cancer. Dissociated integrin β4 directly binds to laminin to activate phosphoinositide 3-OH kinase (PI3K)/AKT signaling [5], which subsequently promotes cell proliferation and survival [6] and cell invasiveness [3, 5]. Loss of integrin β4 reduced tumorigenicity in the ERα-positive breast cancer cell line MCF-7 and even induced apoptosis under estrogen deprivation [11]. It remains unknown how ERα activates integrin β4 signaling
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