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Requirement for both Shc and phosphatidylinositol 3' kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis.

ABSTRACT: Transgenic mice expressing the polyomavirus (PyV) middle T antigen (MT) develop multifocal mammary tumors which frequently metastasize to the lung. The potent transforming activity of PyV MT is correlated with its capacity to activate and associate with a number of signaling molecules, including the Src family tyrosine kinases, the 85-kDa Src homology 2 subunit of the phosphatidylinositol 3' (PI-3') kinase, and the Shc adapter protein. To uncover the role of these signaling proteins in MT-mediated mammary tumorigenesis, we have generated transgenic mice that express mutant PyV MT antigens decoupled from either the Shc or the PI-3' kinase signaling pathway. In contrast to the rapid induction of metastatic mammary tumors observed in the strains expressing wild-type PyV MT, mammary epithelial cell-specific expression of either mutant PyV MT resulted in the induction of extensive mammary epithelial hyperplasias. The mammary epithelial hyperplasias expressing the mutant PyV MT defective in recruiting the PI-3' kinase were highly apoptotic, suggesting that recruitment of PI-3' kinase by MT affects cell survival. Whereas the initial phenotypes observed in both strains were global mammary epithelial hyperplasias, focal mammary tumors eventually arose in all female transgenic mice. Genetic and biochemical analyses of tumorigenesis in the transgenic strains expressing the PyV MT mutant lacking the Shc binding site revealed that a proportion of the metastatic tumors arising in these mice displayed evidence of reversion of the mutant Shc binding site. In contrast, no evidence of reversion of the PI-3' kinase binding site was noted in tumors derived from the strains expressing the PI-3' kinase binding site MT mutant. Tumor progression in both mutant strains was further correlated with upregulation of the epidermal growth factor receptor family members which are known to couple to the PI-3' kinase and Shc signaling pathways. Taken together, these observations suggest that PyV MT-mediated tumorigenesis requires activation of both Shc and PI-3' kinase, which appear to be required for stimulation of cell proliferation and survival signaling pathways, respectively.

SUBMITTER: Webster MA

PROVIDER: S-EPMC121489 | biostudies-other | 1998 Apr

REPOSITORIES: biostudies-other

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Requirement for both Shc and phosphatidylinositol 3' kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis.

Webster M A MA Hutchinson J N JN Rauh M J MJ Muthuswamy S K SK Anton M M Tortorice C G CG Cardiff R D RD Graham F L FL Hassell J A JA Muller W J WJ

Molecular and cellular biology 19980401 4

Transgenic mice expressing the polyomavirus (PyV) middle T antigen (MT) develop multifocal mammary tumors which frequently metastasize to the lung. The potent transforming activity of PyV MT is correlated with its capacity to activate and associate with a number of signaling molecules, including the Src family tyrosine kinases, the 85-kDa Src homology 2 subunit of the phosphatidylinositol 3' (PI-3') kinase, and the Shc adapter protein. To uncover the role of these signaling proteins in MT-mediat ...[more]

PMID: 9528804

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Project description:Overexpression of the NEDD9/HEF1/Cas-L scaffolding protein is frequent, and drives invasion and metastasis in breast, head and neck, colorectal, melanoma, lung and other types of cancer. We have examined the consequences of genetic ablation of Nedd9 in the MMTV-HER2/ERBB2/neu mouse mammary tumor model. Unexpectedly, we found that only a limited effect on metastasis in MMTV-neu;Nedd9(-/-) mice compared with MMTV-neu;Nedd9(+/+) mice, but instead a dramatic reduction in tumor incidence (18 versus 80%), and a significantly increased latency until tumor appearance. Orthotopic reinjection and tail-vein injection of cells arising from tumors, coupled with in vivo analysis, indicated tumors arising in MMTV-neu;Nedd9(-/-) mice had undergone mutational selection that overcame the initial requirement for Nedd9. To better understand the defects in early tumor growth, we compared mammary progenitor cell pools from MMTV-neu;Nedd9(-/-) versus MMTV-neu;Nedd9(+/+) mice. The MMTV-neu;Nedd9(-/-) genotype selectively reduced both the number and colony-forming potential of mammary luminal epithelial progenitor cells, while not affecting basal epithelial progenitors. MMTV-neu;Nedd9(-/-) mammospheres had striking defects in morphology and cell polarity. All of these defects were seen predominantly in the context of the HER2/neu oncogene, and were not associated with randomization of the plane of mitotic division, but rather with depressed expression the cell attachment protein FAK, accompanied by increased sensitivity to small molecule inhibitors of FAK and SRC. Surprisingly, in spite of these significant differences, only minimal changes were observed in the gene expression profile of Nedd9(-/-) mice, indicating critical Nedd9-dependent differences in cell growth properties were mediated via post-transcriptional regulation of cell signaling. Coupled with emerging data indicating a role for NEDD9 in progenitor cell populations during the morphogenesis of other tissues, these results indicate a functional requirement for NEDD9 in the growth of mammary cancer progenitor cells.

Project description:IntroductionBreast cancer exhibits significant molecular, histological, and pathological diversity. Factors that impact this heterogeneity are poorly understood; however, transformation of distinct normal cell populations of the breast may generate different tumor phenotypes. Our previous study demonstrated that the polyomavirus middle T antigen (PyMT) oncogene can establish diverse tumor subtypes when broadly expressed within mouse mammary epithelial cells. In the present study, we assessed the molecular, histological, and metastatic outcomes in distinct mammary cell populations transformed with the PyMT gene.MethodsIsolated mouse mammary epithelial cells were transduced with a lentivirus encoding PyMT during an overnight infection and then sorted into hormone receptor-positive luminal (CD133+), hormone receptor-negative luminal (CD133-), basal, and stem cell populations using the cell surface markers CD24, CD49f, and CD133. Each population was subsequently transplanted into syngeneic cleared mouse mammary fat pads to generate tumors. Tumors were classified by histology, estrogen receptor status, molecular subtype, and metastatic potential to investigate whether transformation of different enriched populations affects tumor phenotype.ResultsAlthough enriched mammary epithelial cell populations showed no difference in either the ability to form tumors or tumor latency, differences in prevalence of solid adenocarcinomas and squamous, papillary, and sebaceous-like tumors were observed. In particular, squamous metaplasia was observed more frequently in tumors derived from basal and stem cells than in luminal cells. Interestingly, both molecularly basal and luminal tumors developed from luminal CD133+, basal, and stem cell populations; however, luminal CD133- cells gave rise exclusively to molecularly basal tumors. Tumors arising from the luminal CD133-, basal, and stem cell populations were highly metastatic; however, luminal CD133+ cells generated tumors that were significantly less metastatic, possibly due to an inability of these tumor cells to escape the primary tumor site.ConclusionsExpression of PyMT within different mammary cell populations influences tumor histology, molecular subtype, and metastatic potential. The data demonstrate that luminal CD133+ cells give rise to less metastatic tumors, luminal CD133- cells preferentially establish basal tumors, and the cell of origin for squamous metaplasia likely resides in the basal and stem cell populations.

Dataset Information

Requirement for both Shc and phosphatidylinositol 3' kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis.

Publications

Requirement for both Shc and phosphatidylinositol 3' kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis.

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