Activated type I TGF beta receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression
- Authors
- Muraoka-Cook, Rebecca S.; Shin, Incheol; Yin, Ji-Ye; Easterly, Emma G.; Barcellos-Hoff, Mary Helen; Yingling, J. M.; Zent, Roy; Arteaga, 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.
- Files in This Item
-
Go to Link
- Appears in
Collections - 서울 자연과학대학 > 서울 생명과학과 > 1. Journal Articles
![qrcode](https://api.qrserver.com/v1/create-qr-code/?size=55x55&data=https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/181389)
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.