1. ¹Terry Fox Molecular Oncology Group and the Bloomfield Center for Research on Aging, Sir Mortimer B Davis Jewish General Hospital, Lady Davis Institute for Medical Research, Montréal, Québec, Canada
2. ²Department of Medicine, McGill University, Montréal, Québec, Canada
3. ³Department of Oncology, McGill University, Montréal, Québec, Canada
4. ⁴Molecular Oncology Group, McGill University Health Centre, Montréal, Québec, Canada
5. ⁵Department of Biochemistry, McGill University, Montréal, Québec, Canada

Correspondence: Professor S Richard, Segal Cancer Centre, Lady Davis Institute for Medical Research, 3755 Côte Ste-Catherine Road, Montréal, Québec, Canada H3T 1E2. E-mail: stephane.richard@mcgill.ca

Received 27 September 2006; Revised 31 May 2007; Accepted 1 June 2007; Published online 9 July 2007.

Abstract

The Src-associated substrate in mitosis Sam68 is a KH type RNA-binding protein known to be a substrate of numerous tyrosine kinases, and often referred to as a STAR (signal transduction activator of RNA) protein. Herein, we observed that Sam68-null mice display mammary gland and the uterine development defects. Moreover, we report that Sam68 haploinsufficiency impedes mammary tumor onset in vivo driven by the potent mammary-targeted polyoma middle T-antigen (MMTV-PyMT) oncogene. The effect was cell autonomous as the Sam68 knockdown in PyMT-transformed cell lines also delayed tumorigenesis and metastasis formation in nude mice. Interestingly, tumor extracts isolated from PyMT/Sam68^+/- mice compared with PyMT/Sam68^+/+ mice contained activated Src and FAK kinases. These findings suggest that Sam68 may be a modulator of tyrosine kinase activity in vivo and a signaling requirement for mammary tumorigenesis and metastasis.