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TGF-β autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression.
| Content Provider | Europe PMC |
|---|---|
| Author | DAROQUI, MARÍA CECILIA VAZQUEZ, PAULA DE KIER JOFFÉ, ELISA BAL BAKIN, ANDREI V. PURICELLI, LYDIA I. |
| Copyright Year | 2012 |
| Abstract | Breast cancer progression and metastasis have been linked to abnormal signaling by transforming growth factor-β (TGF-β) cytokines. In early-stage breast cancers, TGF-β exhibits tumor suppressor activity by repressing cell proliferation and inducing cell death, whereas in advanced-stage tumors, TGF-β promotes invasion and metastatic dissemination. The molecular mechanisms underlying pro-oncogenic activities of TGF-β are not fully understood. The present study validates the role of TGF-β signaling in cancer progression and explores mediators of pro-oncogenic TGF-β activities using the LM3 mammary adenocarcinoma cell line, derived from a spontaneous murine mammary adenocarcinoma. Expression of kinase-inactive TGF-β receptors decreased both basal and TGF-β-induced invasion. Analysis of signal transduction mediators showed that p38MAPK and MEK contribute to TGF-β stimulation of cell motility and invasion. TGF-β disrupted the epithelial actin structures supporting cell-cell adhesions, and increased linear actin filaments. Moreover, MEK and p38MAPK pathways showed opposite effects on actin remodeling in response to TGF-β. Blockade of Raf-MEK signaling enhanced TGF-β induction of actin stress-fibers whereas p38MAPK inhibitors blocked this effect. A novel observation was made that TGF-β rapidly activates the actin nucleation Arp2/3 complex. In addition, TGF-β stimulated matrix metalloproteinase MMP-9 secretion via a MAPK-independent pathway. Experiments using syngeneic mice showed that kinase-inactive TGF-β receptors inhibit the first stages of LM3 tumor growth in vivo. Our studies demonstrate that autocrine TGF-β signaling contributes to the invasive behavior of mammary carcinoma cells. Moreover, we show that both MAPK-dependent and -independent pathways are necessary for TGF-β-induced effects. Therefore, MEK-ERK and p38 MAPK pathways are potential venues for therapeutic intervention in pro-oncogenic TGF-β signaling. |
| ISSN | 1021335X |
| Journal | Oncology Reports |
| Volume Number | 28 |
| PubMed Central reference number | PMC3981025 |
| Issue Number | 2 |
| PubMed reference number | 22614218 |
| e-ISSN | 17912431 |
| DOI | 10.3892/or.2012.1813 |
| Language | English |
| Publisher | D.A. Spandidos |
| Publisher Date | 2012-05-14 |
| Access Restriction | Open |
| Rights License | This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited. Copyright © 2012, Spandidos Publications |
| Subject Keyword | transforming growth factor-β migration invasion matrix metalloproteinase-9 actin cytoskeleton mammary adenocarcinoma |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cancer Research Oncology |
