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Expression of a phosphorylated substrate domain of p130Cas promotes PyMT-induced c-Src-dependent murine breast cancer progression.
Expression of a phosphorylated substrate domain of p130Cas promotes PyMT-induced c-Src-dependent murine breast cancer progression.
- Source :
-
Carcinogenesis [Carcinogenesis] 2013 Dec; Vol. 34 (12), pp. 2880-90. Date of Electronic Publication: 2013 Jul 03. - Publication Year :
- 2013
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Abstract
- Elevated expression of p130Cas (Crk-associated substrate)/BCAR1 (breast cancer antiestrogen resistance 1) in human breast tumors is a marker of poor prognosis and poor overall survival. p130Cas is a downstream target of the tyrosine kinase c-Src. Signaling mediated by p130Cas through its phosphorylated substrate domain (SD) and interaction with effector molecules directly promotes tumor progression. We previously developed a constitutively phosphorylated p130Cas SD molecule, Src*/SD (formerly referred to as Src*/CasSD), which acts as decoy molecule and attenuates the transformed phenotype in v-crk-transformed murine fibroblasts and human breast cancer cells. To test the function of this molecule in vivo, we established mouse mammary tumor virus (MMTV)-long terminal repeat-Src*/SD transgenic mice in which mammary gland development and tumor formation were analyzed. Transgenic expression of the Src*/SD molecule under the MMTV-long terminal repeat promoter did not interfere with normal mammary gland development or induce tumors in mice observed for up to 11 months. To evaluate the effects of the Src*/SD molecule on tumor development in vivo, we utilized the MMTV-polyoma middle T-antigen (PyMT) murine breast cancer model that depends on c-Src. PyMT mice crossed with Src*/SD mice displayed accelerated tumor formation. The earlier onset of tumors can be explained by the interaction of the Src* domain with PyMT and targeting the fused phosphorylated SD to the membrane. At membrane compartments, it might integrate membrane-associated active signaling complexes leading to increased proliferation measured by phospho-Histone H3 staining. Although these results were unexpected, they emphasize the importance of preventing the membrane association of Src*/SD when employed as decoy molecule.
- Subjects :
- Animals
Breast Neoplasms metabolism
Carcinogenesis genetics
Carcinogenesis pathology
Crk-Associated Substrate Protein metabolism
Disease Progression
Female
Fibroblasts metabolism
Fibroblasts pathology
Mammary Glands, Animal metabolism
Mammary Glands, Animal pathology
Mammary Neoplasms, Experimental genetics
Mammary Neoplasms, Experimental metabolism
Mammary Neoplasms, Experimental pathology
Mammary Tumor Virus, Mouse genetics
Mammary Tumor Virus, Mouse metabolism
Mice
Mice, Transgenic genetics
Mice, Transgenic metabolism
Rats
Breast Neoplasms genetics
Breast Neoplasms pathology
Crk-Associated Substrate Protein genetics
Genes, src genetics
Phosphorylation genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2180
- Volume :
- 34
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Carcinogenesis
- Publication Type :
- Academic Journal
- Accession number :
- 23825155
- Full Text :
- https://doi.org/10.1093/carcin/bgt238