Transforming growth factor-beta can suppress tumorigenesis through effects on the putative cancer stem or early progenitor cell and committed progeny in a breast cancer xenograft model.
The transforming growth factor-beta (TGF-beta) pathway has tumor-suppressor activity in many epithelial tissues. Because TGF-beta is a potent inhibitor of epithelial cell proliferation, it has been widely assumed that this property underlies the tumor-suppressor effect. Here, we have used a xenograft model of breast cancer to show that endogenous TGF-beta has the potential to suppress tumorigenesis through a novel mechanism, involving effects at two distinct levels in the hierarchy of cellular progeny that make up the epithelial component of the tumor. First, TGF-beta reduces the size of the putative cancer stem or early progenitor cell population, and second it promotes differentiation of a more committed, but highly proliferative, progenitor cell population to an intrinsically less proliferative state. We further show that reduced expression of the type II TGF-beta receptor correlates with loss of luminal differentiation in a clinical breast cancer cohort, suggesting that this mechanism may be clinically relevant. At a molecular level, the induction of differentiation by TGF-beta involves down-regulation of Id1, and forced overexpression of Id1 can promote tumorigenesis despite persistence of the antiproliferative effect of TGF-beta. These data suggest new roles for the TGF-beta pathway in regulating tumor cell dynamics that are independent of direct effects on proliferation.
Tang
Binwu
B
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892, USA.
Yoo
Naomi
N
Vu
Mary
M
Mamura
Mizuko
M
Nam
Jeong-Seok
JS
Ooshima
Akira
A
Du
Zhijun
Z
Desprez
Pierre-Yves
PY
Anver
Miriam R
MR
Michalowska
Aleksandra M
AM
Shih
Joanna
J
Parks
W Tony
WT
Wakefield
Lalage M
LM
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000172:deficiency; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000172:deficiency; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000502:physiology*; D014183:Transplantation, Heterologous
C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II