Rebecca Cook
Faculty Member
Last active: 4/15/2019

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

Muraoka-Cook RS, Shin I, Yi JY, Easterly E, Barcellos-Hoff MH, Yingling JM, Zent R, Arteaga CL
Oncogene. 2006 25 (24): 3408-23

PMID: 16186809 · DOI:10.1038/sj.onc.1208964

We have examined the effects of transforming growth factor-beta (TGFbeta) 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 TGFbeta-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) TGFbeta can signal to PI3K/Akt and enhance mammary epithelial cell survival in vivo before cytological or histological evidence of transformation, and (2) TGFbeta signaling can provide epithelial cells with a 'gain-of-function' effect that synergizes with oncogene-induced transformation.

MeSH Terms (14)

Activin Receptors, Type I Animals Apoptosis Cell Survival Disease Progression Genes, Reporter Mammary Glands, Animal Mammary Neoplasms, Animal Mice Neoplasm Metastasis Phosphatidylinositol 3-Kinases Protein-Serine-Threonine Kinases Receptor, Transforming Growth Factor-beta Type I Receptors, Transforming Growth Factor beta

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