Activated type I TGFbeta receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression.
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.
Muraoka-Cook
R S
RS
Department of Cancer Biology, Vanderbilt University school of Medicine, Nashville, TN 37232-6307, USA.
Shin
I
I
Yi
J Y
JY
Easterly
E
E
Barcellos-Hoff
M H
MH
Yingling
J M
JM
Zent
R
R
Arteaga
C L
CL
D030201:Activin Receptors, Type I / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D018450:Disease Progression; D017930:Genes, Reporter; D008321:Mammary Glands, Animal / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism
D030201:Activin Receptors, Type I; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; C000625842:Tgfbr1 protein, mouse