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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Kumbrink, Joerg de la Cueva, Ana Soni, Shefali Sailer, Nadja Kirsch, Kathrin H. |
| Description | Country affiliation: United States Author Affiliation: Kumbrink J ( Department of Biochemistry, Boston University School of Medicine, 72 E. Concord Street, Boston, MA, 02118, USA.); de la Cueva A ( Department of Medicine III, University Hospital Grosshadern, University of Munich, Munich, Germany.); Soni S ( Institute of Pathology, University of Munich, Munich, Germany.); Sailer N ( Department of Biochemistry, Boston University School of Medicine, 72 E. Concord Street, Boston, MA, 02118, USA.); Kirsch KH ( Department of Biochemistry, Boston University School of Medicine, 72 E. Concord Street, Boston, MA, 02118, USA.) |
| Abstract | Elevated p130Cas (Crk-associated substrate) levels are found in aggressive breast tumors and are associated with poor prognosis and resistance to standard therapeutics in patients. p130Cas signals majorly through its phosphorylated substrate domain (SD) that contains 15 tyrosine motifs (YxxP) which recruit effector molecules. Tyrosine phosphorylation of p130Cas is important for mediating migration, invasion, tumor promotion, and metastasis. We previously developed a Src*/SD fusion molecule approach, where the SD is constitutively phosphorylated. In a polyoma middle T-antigen (PyMT)/Src*/SD double-transgenic mouse model, Src*/SD accelerates PyMT-induced tumor growth and promotes a more aggressive phenotype. To test whether Src*/SD also drives metastasis and which of the YxxP motifs are involved in this process, full-length and truncated SD molecules fused to Src* were expressed in breast cancer cells. The functionality of the Src*/SD fragments was analyzed in vitro, and the active proteins were tested in vivo in an orthotopic mouse model. Breast cancer cells expressing the full-length SD and the functional smaller SD fragment (spanning SD motifs 6-10) were injected into the mammary fat pads of mice. The tumor progression was monitored by bioluminescence imaging and caliper measurements. Compared with control animals, the complete SD promoted primary tumor growth and an earlier onset of metastases. Importantly, both the complete and truncated SD significantly increased the occurrence of metastases to multiple organs. These studies provide strong evidence that the phosphorylated p130Cas SD motifs 6-10 (Y236, Y249, Y267, Y287, and Y306) are important for driving mammary carcinoma progression. |
| File Format | HTM / HTML |
| ISSN | 10104283 |
| Issue Number | 8 |
| Journal | Tumor Biology |
| Volume Number | 37 |
| e-ISSN | 14230380 |
| Language | English |
| Publisher | Springer |
| Publisher Date | 2016-08-01 |
| Publisher Place | Netherlands |
| Access Restriction | Subscribed |
| Content Type | Text |
| Resource Type | Article |
| Subject | Medicine Cancer Research |
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