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 language | English (US) |
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Pages (from-to) | 3408-3423 |
Number of pages | 16 |
Journal | Oncogene |
Volume | 25 |
Issue number | 24 |
DOIs | |
State | Published - Jun 8 2006 |
Keywords
- Involution
- Mammary cancer
- Oncogenes
- PI-3 kinase
- TGFβ
- Transgenic mice
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research