title: Estrogen Enhances the Cell Viability and Motility of Breast Cancer Cells through the ERα-ΔNp63-Integrin β4 Signaling Pathway.
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.
authors: Department of Pathology, and Graduate Institute of Pathology and Parasitology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors: Jar-Yi
authors: JY
authors: Ho
authors: Department of Obstetrics & Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors: Fung-Wei
authors: FW
authors: Chang
authors: Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei, Taiwan.
authors: Fong Shung
authors: FS
authors: Huang
authors: Division of Urology, Department of Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan.
authors: Jui-Ming
authors: JM
authors: Liu
authors: Department of Emergency Medicine national Taiwan University Hospital, Taipei, Taiwan.
authors: Yueh-Ping
authors: YP
authors: Liu
authors: Division of Medical Genetics, Department of Pediatrics, Chang Gung Children's Hospital, Taoyuan, Taiwan.
authors: Shu-Pin
authors: SP
authors: Chen
authors: Department of Obstetrics & Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors: Yung-Liang
authors: YL
authors: Liu
authors: Institute of Biotechnology, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei, Taiwan.
authors: Kuan-Chen
authors: KC
authors: Cheng
authors: Department of Pathology, and Graduate Institute of Pathology and Parasitology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.|Department of Emergency Medicine national Taiwan University Hospital, Taipei, Taiwan.
authors: Cheng-Ping
authors: CP
authors: Yu
authors: Department of Pathology, and Graduate Institute of Pathology and Parasitology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.|Biobank Management Center of Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors: Ren-Jun
authors: RJ
authors: Hsu
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D039663:Integrin beta4 / Q000096:biosynthesis / Q000235:genetics*; D061986:MCF-7 Cells; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D039663:Integrin beta4; D034741:RNA, Small Interfering; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins