Affiliation:
1. Departments of Cancer Biology, Cell and Developmental Biology, and Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160
Abstract
ABSTRACT
We have previously shown that c-MYC-induced mammary tumorigenesis in mice proceeds via a preferred secondary pathway involving spontaneous activating mutations in
Kras2
(C. M. D'Cruz, E. J. Gunther, R. B. Boxer, J. L. Hartman, L. Sintasath, S. E. Moody, J. D. Cox, S. I. Ha, G. K. Belka, A. Golant, R. D. Cardiff, and L. A. Chodosh, Nat. Med. 7:235-239, 2001). In contrast, we now demonstrate that Wnt1-induced mammary tumorigenesis proceeds via a pathway that preferentially activates
Hras1.
In addition, we find that expression of oncogenic forms of
Kras2
and
Hras1
from their endogenous promoters has markedly different consequences for the progression of tumors to oncogene independence. Spontaneous activating
Kras2
mutations occurring in either MYC- or Wnt1-induced tumors were strongly associated with oncogene-independent tumor growth following MYC or Wnt1 downregulation. In contrast,
Hras1
-mutant Wnt1-induced tumors consistently remained oncogene dependent. Additionally,
Kras2
-mutant tumors exhibited substantially higher levels of ras-GTP, phospho-Erk1/2, and phospho-Mek1/2 compared to
Hras1
-mutant tumors, suggesting the involvement of the ras/mitogen-activated protein kinase (MAPK) pathway in the acquisition of oncogene independence. Consistent with this, by use of carcinogen-induced
ras
mutations as well as knock-in mice harboring a latent activated
Kras2
allele, we demonstrate that Kras2 activation strongly synergizes with both c-MYC and Wnt1 in mammary tumorigenesis and promotes the progression of tumors to oncogene independence. Together, our findings support a model for tumorigenesis in which c-MYC and Wnt1 select for the outgrowth of cells harboring mutations in specific
ras
isoforms and that these secondary mutations, in turn, determine the extent of ras/MAPK pathway activation and the potential for oncogene-independent growth.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
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