title: Significance of PELP1 in ER-negative breast cancer metastasis.
abstract: Breast cancer metastasis is a major clinical problem. The molecular basis of breast cancer progression to metastasis remains poorly understood. PELP1 is an estrogen receptor (ER) coregulator that has been implicated as a proto-oncogene whose expression is deregulated in metastatic breast tumors and whose expression is retained in ER-negative tumors. We examined the mechanism and significance of PELP1-mediated signaling in ER-negative breast cancer progression using two ER-negative model cells (MDA-MB-231 and 4T1 cells) that stably express PELP1-shRNA. These model cells had reduced PELP1 expression (75% of endogenous levels) and exhibited less propensity to proliferate in growth assays in vitro. PELP1 downregulation substantially affected migration of ER-negative cells in Boyden chamber and invasion assays. Using mechanistic studies, we found that PELP1 modulated expression of several genes involved in the epithelial mesenchymal transition (EMT), including MMPs, SNAIL, TWIST, and ZEB. In addition, PELP1 knockdown reduced the in vivo metastatic potential of ER-negative breast cancer cells and significantly reduced lung metastatic nodules in a xenograft assay. These results implicate PELP1 as having a role in ER-negative breast cancer metastasis, reveal novel mechanism of coregulator regulation of metastasis via promoting cell motility/EMT by modulating expression of genes, and suggest PELP1 may be a potential therapeutic target for metastatic ER-negative breast cancer.
authors.affiliation: Department of Obstetrics and Gynecology and Cancer Therapy & Research Center, UT Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Sudipa
authors.initials: S
authors.lastname: Roy
authors.forename: Dimple
authors.initials: D
authors.lastname: Chakravarty
authors.forename: Valerie
authors.initials: V
authors.lastname: Cortez
authors.forename: Keya
authors.initials: K
authors.lastname: De Mukhopadhyay
authors.forename: Abhik
authors.initials: A
authors.lastname: Bandyopadhyay
authors.forename: Jung-Mo
authors.initials: JM
authors.lastname: Ahn
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Raj
authors.forename: Rajeshwar R
authors.initials: RR
authors.lastname: Tekmal
authors.forename: LuZhe
authors.initials: L
authors.lastname: Sun
authors.forename: Ratna K
authors.initials: RK
authors.lastname: Vadlamudi
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D056970:Co-Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D056970:Co-Repressor Proteins; C000715470:MAS1 protein, human; C438485:PELP1 protein, human; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D014157:Transcription Factors
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