title: TGF-β induced TMEPAI/PMEPA1 inhibits canonical Smad signaling through R-Smad sequestration and promotes non-canonical PI3K/Akt signaling by reducing PTEN in triple negative breast cancer.
abstract: TMEPAI (transmembrane prostate androgen-induced) is amplified at genomic, transcript and protein levels in triple-negative breast cancers and promotes TGF-β dependent growth, motility and invasion. Tumor promotion by TMEPAI depends on two different but related actions on TGF-β signaling. Firstly, TMEPAI binds and sequesters regulatory Smads2/3 and thereby decreases growth suppressive signaling by TGF-β. Secondly, increased expression of TMEPAI decreases PTEN (phosphatase and tensin homolog) abundance, and thereby increases TGF-β dependent tumor promotive PI3K/Akt signaling. These actions of TMEPAI give rise to increased cell proliferation and motility. Moreover, signaling alterations produced by high TMEPAI were associated with oncogenic Snail expression and lung metastases. Finally, an inverse correlation between TMEPAI and PTEN levels was confirmed in triple negative breast cancer tumor samples. Together, our findings suggest that TMEPAI has dually critical roles to promote TGF-β dependent cancer cell growth and metastasis. Thus, redirected TGF-β signaling through TMEPAI may play a pivotal role in TGF-β mediated tumor promotion.
authors.affiliation: From the Department of Pathology, UT Health Science Center at San Antonio, TX.
authors.forename: Prajjal K
authors.initials: PK
authors.lastname: Singha
authors.affiliation: Department of Med/Hematology & Med Oncology, UT Health Science Center at San Antonio, TX.
authors.forename: Srilakshmi
authors.initials: S
authors.lastname: Pandeswara
authors.affiliation: From the Department of Pathology, UT Health Science Center at San Antonio, TX.
authors.forename: Hui
authors.initials: H
authors.lastname: Geng
authors.affiliation: From the Department of Pathology, UT Health Science Center at San Antonio, TX.
authors.forename: Rongpei
authors.initials: R
authors.lastname: Lan
authors.affiliation: From the Department of Pathology, UT Health Science Center at San Antonio, TX.
authors.forename: Manjeri A
authors.initials: MA
authors.lastname: Venkatachalam
authors.affiliation: From the Department of Pathology, UT Health Science Center at San Antonio, TX.
authors.forename: Pothana
authors.initials: P
authors.lastname: Saikumar
keywords: PMEPA1; PTEN; Smad; TGF-β; TMEPAI; Triple Negative Breast Cancer (TNBC)