20q11.23

ASV,SRC1,THC6,c-SRC,p60-Src

Cancer

Elevated Src expression and/or activity has been reported in many different cancer types, where it may associate with poor clinical prognosis (Irby and Yeatman, 2000). Increased Src kinase activity in cancer is likely to arise from the deregulation of Src expression and/or activation mechanisms rather than the presence of activating mutations, since genetic mutations of this kind are rarely reported for Src (see above). Whereas constitutively activated forms of Src are transforming, wild-type Src has a relatively low transformation potential suggesting that Src may act to facilitate intracellular signalling through regulation, either directly or indirectly, of other signalling proteins.

Colorectal cancer

Increased Src activity has been widely described in colorectal tumour tissue compared with normal epithelia and within colon polyps, particularly those displaying a malignant phenotype (DeSeau et al., 1987; Cartwright et al., 1994). In colorectal cancer tissue studies, elevated Src kinase activity is associated with a poor clinical outcome (Aligayer et al., 2002). In vitro studies suggest that in colon cancer, Src may contribute more to disease spread than to increased proliferation (Jones et al., 2002).

Breast cancer

Src kinase activity is increased in breast cancer tissue compared to normal tissues (Verbeek et al., 1996). In vivo animal models suggest that Src activity is elevated in breast tumours overexpressing HER2 and interaction between Src and erbB family members may promote the development of a more aggressive disease clinically (Biscardi et al., 2000; Tan et al., 2005). Physical interactions between Src and growth factor receptors are reported in breast cancer tissues and cells, particularly with receptor tyrosine kinases of the EGFR family allowing Src to regulate signalling pathways that may contribute to aggressive breast cancer cell behaviour. Src is also intimately involved with Her2 pathway signalling in breast cancer, the result of which is the promotion of an invasive phenotype (Vadlamudi et al., 2003; Tan et al., 2005).
Oestrogenic signalling plays a critical role in promoting breast cancer cell growth where ligand-induced activation of oestrogen receptors (ERs) results in gene transcription mediated by the ER, in complex with various co-activators/co-repressor molecules. In such cases, Src is able to potentiate ER-mediated, AF-1 dependent gene transcription through indirect phosphorylation of nuclear ER via ERK1/ ERK2 (Feng et al., 2001) and Akt (Campbell et al., 2001; Shah et al., 2005) and through regulation of FAK-p130CAS-JNK signalling pathway activity and the subsequent activation of co-activator molecules including CBP ( PAG1) and GRIP1 ( NCOA2). Furthermore, Src appears to mediate non-genomic ER signalling through ERK and Akt pathways (Castoria et al., 2001; Wessler et al., 2006) to regulate cellular proliferation and survival (Castoria et al., 1999; Migliaccio et al., 2000). That Src is involved in both EGFR/Her2 and ER signalling has led to Src being implicated in growth factor-ER cross talk mechanisms in breast cancer and the development of endocrine resistance (Arpino et al., 2008; Massarweh and Schiff, 2006; Hiscox et al., 2006; Hiscox et al., 2009).

Hematopoietic cancers

The majority of Src family kinases are highly expressed in cells of a hematopoietic origin where they are suggested to regulate growth and proliferation. Src itself is, along with related family kinase members, are implicated in imatinib-resistant, BCR-ABL-expressing CML (Li, 2008).

Other tumour types

Src protein and activity have been identified as being increased in a number of other tumour types including gastric, pancreatic, lung and ovarian tumours compared to normal tissue suggesting a possible role for Src in these tumours.