Journal article
p130Cas Is Required for Mammary Tumor Growth and Transforming Growth Factor-beta-mediated Metastasis through Regulation of Smad2/3 Activity
The Journal of biological chemistry, Vol.284(49), pp.34145-34156
12/04/2009
DOI: 10.1074/jbc.M109.023614
PMCID: PMC2797185
PMID: 19822523
Abstract
During breast cancer progression, transforming growth factor-beta (TGF-beta) switches from tumor suppressor to a prometastatic molecule. Several recent studies suggest that this conversion in TGF-beta function depends upon fundamental changes in the TGF-beta signaling system. We show here that these changes in TGF-beta signaling are concomitant with aberrant expression of the focal adhesion protein, p130Cas. Indeed, elevating expression of either the full-length (FL) or just the carboxyl terminus (CT) of p130Cas in mammary epithelial cells (MECs) diminished the ability of TGF-beta 1 to activate Smad2/3, but increased its coupling to p38 MAPK. This shift in TGF-beta signaling evoked (i) resistance to TGF-beta-induced growth arrest, and (ii) acinar filling upon three-dimensional organotypic cultures of p130Cas-FL or -CT expressing MECs. Furthermore, rendering metastatic MECs deficient in p130Cas enhanced TGF-beta-stimulated Smad2/3 activity, which restored TGF-beta-induced growth inhibition both in vitro and in mammary tumors produced in mice. Additionally, whereas elevating T beta R-II expression in metastatic MECs had no affect on their phosphorylation of Smad2/3, this event markedly enhanced their activation of p38 MAPK, leading to increased MEC invasion and metastasis. Importantly, depleting p130Cas expression in T beta R-II-expressing metastatic MECs significantly increased their activation of Smad2/3, which (i) reestablished the physiologic balance between canonical and noncanonical TGF-beta signaling, and (ii) reversed cellular invasion and early mammary tumor cell dissemination stimulated by TGF-beta. Collectively, our findings identify p130Cas as a molecular rheostat that regulatesthedelicatebalancebetweencanonicalandnoncanonical TGF-beta signaling, a balance that is critical to maintaining the tumor suppressor function of TGF-beta during breast cancer progression.
Details
- Title: Subtitle
- p130Cas Is Required for Mammary Tumor Growth and Transforming Growth Factor-beta-mediated Metastasis through Regulation of Smad2/3 Activity
- Creators
- Michael K. Wendt - University of Colorado Anschutz Medical CampusJason A. Smith - University of Colorado Anschutz Medical CampusWilliam P. Schiemann - University of Colorado Anschutz Medical Campus
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.284(49), pp.34145-34156
- DOI
- 10.1074/jbc.M109.023614
- PMID
- 19822523
- PMCID
- PMC2797185
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Amer Soc Biochemistry Molecular Biology Inc
- Number of pages
- 12
- Grant note
- PF-09-120-01-CSM / American Cancer Society BC084651 / Department of Defense; United States Department of Defense CA129359 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01CA129359 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) BCTR0706967 / Komen Foundation; Susan G. Komen Breast Cancer Foundation
- Language
- English
- Date published
- 12/04/2009
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984459619602771
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