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

Authors
Muraoka-Cook, Rebecca S.Shin, IncheolYin, Ji-YeEasterly, Emma G.Barcellos-Hoff, Mary HelenYingling, J. M.Zent, RoyArteaga, Carlos L.
Issue Date
Jun-2006
Publisher
NATURE PUBLISHING GROUP
Keywords
TGF beta; mammary cancer; transgenic mice; PI-3 kinase; involution; oncogenes
Citation
ONCOGENE, v.25, no.24, pp.3408 - 3423
Indexed
SCIE
SCOPUS
Journal Title
ONCOGENE
Volume
25
Number
24
Start Page
3408
End Page
3423
URI
https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/181389
DOI
10.1038/sj.onc.1208964
ISSN
0950-9232
Abstract
We have examined the effects of transforming growth factor-beta (TGF beta) signaling on mammary epithelial cell survival. Transgenic mice expressing an active mutant of Alk5 in the mammary gland (MMTV-Alk5(T204D)) 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 TGF beta-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 Alk5(T204D)-expressing mice did not develop mammary tumors, bigenic MMTV-Alk(T204D) x Neu mice developed cancers that were more metastatic than those occurring in MMTV-Neu transgenics. These data suggest that (1) TGF beta can signal to PI3K/Akt and enhance mammary epithelial cell survival in vivo before cytological or histological evidence of transformation, and (2) TGF beta signaling can provide epithelial cells with a 'gain-of-function' effect that synergizes with oncogene-induced transformation.
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