Faculty Collaboration Database

Biological responses to TGF-β in the mammary epithelium show a complex dependency on Smad3 gene dosage with important implications for tumor progression. Mol Cancer Res 2012 Oct;10(10):1389-99

Date

08/11/2012

Pubmed ID

22878587

Pubmed Central ID

PMC3475765

DOI

10.1158/1541-7786.MCR-12-0136-T

Scopus ID

2-s2.0-84867636022 (requires institutional sign-in at Scopus site)   17 Citations

Abstract

TGF-β plays a dual role in epithelial carcinogenesis with the potential to either suppress or promote tumor progression. We found that levels of Smad3 mRNA, a critical mediator of TGF-β signaling, are reduced by approximately 60% in human breast cancer. We therefore used conditionally immortalized mammary epithelial cells (IMEC) of differing Smad3 genotypes to quantitatively address the Smad3 requirement for different biologic responses to TGF-β. We found that a two-fold reduction in Smad3 gene dosage led to complex effects on TGF-β responses; the growth-inhibitory response was retained, the pro-apoptotic response was lost, the migratory response was reduced, and the invasion response was enhanced. Loss of the pro-apoptotic response in the Smad3(+/-) IMECs correlated with loss of Smad3 binding to the Bcl-2 locus, whereas retention of the growth-inhibitory response in Smad3 IMECs correlated with retention of Smad3 binding to the c-Myc locus. Addressing the integrated outcome of these changes in vivo, we showed that reduced Smad3 levels enhanced metastasis in two independent models of metastatic breast cancer. Our results suggest that different biologic responses to TGF-β in the mammary epithelium are differentially affected by Smad3 dosage and that a mere two-fold reduction in Smad3 is sufficient to promote metastasis.

Author List

Kohn EA, Yang YA, Du Z, Nagano Y, Van Schyndle CM, Herrmann MA, Heldman M, Chen JQ, Stuelten CH, Flanders KC, Wakefield LM

Author

Catherine Van Schyndle Nurse Practitioner in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Breast Neoplasms
Cell Transformation, Neoplastic
Disease Progression
Enhancer Elements, Genetic
Epithelium
Female
Gene Dosage
Gene Expression Regulation, Neoplastic
Humans
Mammary Glands, Animal
Mammary Glands, Human
Mice
Neoplasm Metastasis
Protein Binding
Proto-Oncogene Proteins c-bcl-2
Proto-Oncogene Proteins c-myc
Smad3 Protein
Transforming Growth Factor beta