title: Inhibition of mTOR signaling reduces PELP1-mediated tumor growth and therapy resistance.
abstract: Proline, Glutamic acid-, and Leucine-rich Protein 1 (PELP1) is a proto-oncogene that modulates estrogen receptor (ER) signaling. PELP1 expression is upregulated in breast cancer, contributes to therapy resistance, and is a prognostic marker of poor survival. In a subset of breast tumors, PELP1 is predominantly localized in the cytoplasm and PELP1 participates in extranuclear signaling by facilitating ER interactions with Src and phosphoinositide 3-kinase (PI3K). However, the mechanism by which PELP1 extranuclear actions contributes to cancer progression and therapy resistance remains unclear. In this study, we discovered that PELP1 cross-talked with the serine/threonine protein kinase mTOR and modulated mTOR signaling. PELP1 knockdown significantly reduced the activation of mTOR downstream signaling components. Conversely, PELP1 overexpression excessively activated mTOR signaling components. We detected the presence of the mTOR signaling complex proteins in PELP1 immunoprecipitates. mTOR-targeting drugs (rapamycin and AZD8055) significantly reduced proliferation of PELP1-overexpressed breast cancer cells in both in vitro and in vivo xenograft tumor models. MCF7 cells that uniquely retain PELP1 in the cytoplasm showed resistance to hormonal therapy and mTOR inhibitors sensitized PELP1cyto cells to hormonal therapy in xenograft assays. Notably, immunohistochemical studies using xenograft tumors derived from PELP1 overexpression model cells showed increased mTOR signaling and inhibition of mTOR rendered PELP1-driven tumors to be highly sensitive to therapeutic inhibition. Collectively, our data identified the PELP1-mTOR axis as a novel component of PELP1 oncogenic functions and suggest that mTOR inhibitor(s) will be effective chemotherapeutic agents for downregulating PELP1 oncogenic functions.
authors.affiliation: Authors' Affiliation: Department of Obstetrics and Gynecology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Gonugunta
authors.affiliation: Authors' Affiliation: Department of Obstetrics and Gynecology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.
authors.forename: Gangadhara R
authors.initials: GR
authors.lastname: Sareddy
authors.affiliation: Authors' Affiliation: Department of Obstetrics and Gynecology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.
authors.forename: Samaya Rajeshwari
authors.initials: SR
authors.lastname: Krishnan
authors.affiliation: Authors' Affiliation: Department of Obstetrics and Gynecology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.
authors.forename: Valerie
authors.initials: V
authors.lastname: Cortez
authors.affiliation: Authors' Affiliation: Department of Obstetrics and Gynecology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.
authors.forename: Sudipa Saha
authors.initials: SS
authors.lastname: Roy
authors.affiliation: Authors' Affiliation: Department of Obstetrics and Gynecology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.
authors.forename: Rajeshwar Rao
authors.initials: RR
authors.lastname: Tekmal
authors.affiliation: Authors' Affiliation: Department of Obstetrics and Gynecology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas vadlamudi@uthscsa.edu.
authors.forename: Ratna K
authors.initials: RK
authors.lastname: Vadlamudi
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics*; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D061986:MCF-7 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D056970:Co-Repressor Proteins; D019869:Phosphatidylinositol 3-Kinases; D000090063:Proto-Oncogene Mas; D011960:Receptors, Estrogen; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C000715470:MAS1 protein, human; C438485:PELP1 protein, human; C546842:MTOR protein, human