Activated type I TGFβ receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression

R. S. Muraoka-Cook, I. Shin, J. Y. Yi, E. Easterly, M. H. Barcellos-Hoff, J. M. Yingling, R. Zent, C. L. Arteaga

Research output: Contribution to journalArticle

110 Scopus citations

Abstract

We have examined the effects of transforming growth factor-beta (TGFβ) signaling on mammary epithelial cell survival. Transgenic mice expressing an active mutant of Alk5 in the mammary gland (MMTV-Alk5T204D) exhibited reduced apoptosis in terminal endbuds and during postlactational involution. Transgene-expressing mammary cells contained lower Smad2/3 and higher c-myc levels than controls, high ligand-independent phosphatidylinositol-3 kinase (PI3K) and Akt activities, and were insensitive to TGFβ-mediated growth arrest. Treatment with a proteasome inhibitor increased Smad2/3 levels and ligand-independent Smad transcriptional reporter activity, as well as reduced both c-myc protein and basal cell proliferation. Treatment with an Alk5 kinase small-molecule inhibitor upregulated Smad2/3 levels, reduced PI3K activity, P-Akt, and c-myc, and inhibited cell survival. Although Alk5T204D- expressing mice did not develop mammary tumors, bigenic MMTV-AlkT204D × Neu mice developed cancers that were more metastatic than those occurring in MMTV-Neu transgenics. These data suggest that (1) TGFβ can signal to PI3K/Akt and enhance mammary epithelial cell survival in vivo before cytological or histological evidence of transformation, and (2) TGFβ signaling can provide epithelial cells with a 'gain-of-function' effect that synergizes with oncogene-induced transformation.

Original languageEnglish (US)
Pages (from-to)3408-3423
Number of pages16
JournalOncogene
Volume25
Issue number24
DOIs
StatePublished - Jun 8 2006

Keywords

  • Involution
  • Mammary cancer
  • Oncogenes
  • PI-3 kinase
  • TGFβ
  • Transgenic mice

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Muraoka-Cook, R. S., Shin, I., Yi, J. Y., Easterly, E., Barcellos-Hoff, M. H., Yingling, J. M., Zent, R., & Arteaga, C. L. (2006). Activated type I TGFβ receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Oncogene, 25(24), 3408-3423. https://doi.org/10.1038/sj.onc.1208964