Mutation of the SRC Gene in Endometrial Carcinoma

Abstract

Recently, an activating mutation of the SRC gene has been implicated in about one-tenth of advanced colon cancers. The SRC 531 mutation results in truncation of SRC directly C-terminal to the regulatory Tyr 530 and appears to activate the Tyr 530. To investigate whether mutation of SRC plays an important role in the development and progression of gynecological tumors, we performed mutational analysis of the entire coding region of SRC in 70 ovarian carcinomas, 68 endometrial carcinomas and 3 endometrial stromal sarcomas by means of polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) followed by nucleotide sequencing and restriction fragment length polymorphism (RFLP) analysis. We found one truncated mutation at codon 531 (Gln to Stop) in an endometrial carcinoma. However, we found no mutation of this gene in ovarian carcinoma or endometrial stromal sarcoma. Our results suggest that mutation of SRC may be implicated in a small proportion of endometrial carcinomas.

Integrin αvβ3 Controls Activity and Oncogenic Potential of Primed c-Src

“…Overexpression of RTKs has been proposed to induce a primed conformation of c-Src by disrupting the intramolecular binding of the SH2 domain to phosphorylated Tyr 530 (19,23). In addition, mutations in the COOH-terminal region of the SRC gene that lead to a primed conformation of c-Src have been detected in a small subset of carcinomas of the colon and the endometrium (26,27). Whatever the mechanism of priming, our findings show that the oncogenic potential of primed c-Src can be strongly enhanced by integrin a v h 3 .…”

“…Increased levels of c-Src and binding of overexpressed RTKs to the c-Src SH2 domain may enhance c-Src priming. In addition, mutations in the SRC gene stabilizing a primed conformation of c-Src through truncation of the regulatory COOH terminus have been detected in colon and endometrial cancer, although such mutations seem to be rare (26)(27)(28)(29).…”

Adhesion signaling by a novel mitotic substrate of src kinases

“…High src activity is characteristic of many common human tumors including colon cancers, breast cancers, lung cancers, sarcomas, and melanomas (Rosen et al, 1986;Cartwright et al, 1989;Ottenhoff-Kalff et al, 1992;Irby and Yeatman, 2000). In a subset of these tumors, this is due to mutational activation of src (Mao et al, 1997;Irby and Fujita, 1999;Sugimura et al, 2000). The interest in determining a src signaling pathway has led to the identification of numerous src substrates involved in diverse cellular functions including growth factor receptor signaling, cytoskeletal organization, cell motility, and adhesion signaling (Erpel and Courtneidge, 1995).…”

Src Family Protein-tyrosine Kinases Alter the Function of PTEN to Regulate Phosphatidylinositol 3-Kinase/AKT Cascades

“…Src has been found to be overexpressed or highly activated in a number of human neoplasmas, including ovary, breast, lung, colon, esophagus, skin, parotid, cervix, and gastric carcinomas, as well as neuroblastomas and myeloproliferative disorders (9 -14). An activated mutation of Src may be present in a number of neoplasms, contributing to their development or progression (15,16). Transgenic mice expressing the polyomavirus middle T oncogene in the mammary epithelium develop multifocal mammary tumors that metastasize with high frequency because of an ability to associate with and activate Src family kinases, phosphatidylinositol 3-kinase (PI3K) 1 and the Shc adapter protein (17)(18)(19)(20).…”