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Sam68 Haploinsufficiency Delays Onset of Mammary Tumorigenesis

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Sam68 Haploinsufficiency Delays Onset of Mammary Tumorigenesis Oncogene (2008) 27, 548–556 & 2008 Nature Publishing Group All rights reserved 0950-9232/08 $30.00 www.nature.com/onc ORIGINAL ARTICLE Sam68 haploinsufficiency delays onset of mammary tumorigenesis and metastasis S Richard1,2,3, G Vogel1,2,3, M-E´ Huot1,2,3, T Guo1,2,3, WJ Muller2,4,5 and KE Lukong1,2,3 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, Montre´al, Que´bec, Canada; 2Department of Medicine, McGill University, Montre´al, Que´bec, Canada; 3Department of Oncology, McGill University, Montre´al, Que´bec, Canada; 4Molecular Oncology Group, McGill University Health Centre, Montre´al, Que´bec, Canada and 5Department of Biochemistry, McGill University, Montre´al, Que´bec, Canada The Src-associated substrate in mitosis Sam68 is a KH domain, proline-rich SH3 (Src homology domain 3)- type RNA-bindingprotein known to be a substrate of binding and SH2-interacting tyrosine-rich motifs (Lu- numerous tyrosine kinases, and often referred to as a kong and Richard, 2003). Sam68 is a substrate of breast STAR (signal transduction activator of RNA) protein. tumor kinase (BRK; Derry et al., 2000), a kinase Herein, we observed that Sam68-null mice display overexpressed in about 60% of breast tumors (Kamalati mammary gland and the uterine development defects. et al., 1996). The tyrosine phosphorylation of Sam68 Moreover, we report that Sam68 haploinsufficiency may be a marker for certain cancers where tyrosine impedes mammary tumor onset in vivo driven by the kinases are induced. Indeed, we have shown that Sam68 potent mammary-targeted polyoma middle T-antigen is a substrate downstream of the epithelial growth factor (MMTV-PyMT) oncogene. The effect was cell autono- (EGF; Lukong et al., 2005) and Sam68 tyrosine mous as the Sam68 knockdown in PyMT-transformed cell phosphorylation is elevated in human breast tumors lines also delayed tumorigenesis and metastasis formation tissues and cell lines (Babic et al., 2004; Lukong et al., in nude mice. Interestingly, tumor extracts isolated from 2005). Consistent with these findings is the elevated PyMT/Sam68 þ /À mice compared with PyMT/Sam68 þ / þ expression of Sam68 observed in prostate cancer tissues mice contained activated Src and FAK kinases. These (Busa et al., 2007). These findings suggest that tyrosine findings suggest that Sam68 may be a modulator of phosphorylation of Sam68 and its expression are tyrosine kinase activity in vivo and a signaling require- required for tumorigenesis. Conversely, the reduced ment for mammary tumorigenesis and metastasis. expression of Sam68 in NIH3T3 cells using a gene trap Oncogene (2008) 27, 548–556; doi:10.1038/sj.onc.1210652; strategy and antisense-induced neoplastic transfor- published online 9 July 2007 mation suggests Sam68 may have tumor suppressor properties (Liu et al., 2000). However, the Sam68À/À Keywords: Sam68; RNA binding; mammary tumorigenesis; mice live to old age (B2 years) and were not prone to Src; metastasis; signaling tumor formation, suggesting that Sam68 is not a tumor suppressor in vivo (Richard et al., 2005). Results Introduction Sam68À/À mice have defects in breast and Sam68, the Src-Associated substrate during Mitosis of uterine development 68 kDa, is a member of the STAR (Signal Transduction Herein, we investigated whether the absence of Sam68 Activator of RNA) family of RNA-binding proteins prevented or accelerated tumorigenesis in vivo, and we proposed to link signaling cascades to RNA metabolism employed the mammary-targeted polyoma middle T (Vernet and Artzt, 1997; Lukong and Richard, 2003). antigen (MMTV-PyMT) mouse model because PyMT These proteins share at least three functional motifs utilizes Src for signaling and induces rapid breast tumors including a K (hnRNP K) homology (KH) RNA- that resemble human breast cancers (Lin et al., 2003). binding domain embedded in a larger domain termed Whole-mount analysis and hematoxylin/eosin staining the GSG (GRP33, Sam68, GLD-1) or the STAR of sections of the fourth inguinal mammary glands of 6- and 12-week-old virgin females from Sam68 þ / þ , Correspondence: Professor S Richard, Segal Cancer Centre, Lady Sam68 þ /À and Sam68À/À mice were performed to Davis Institute for Medical Research, 3755 Coˆ te Ste-Catherine Road, examine mammary development (Figure 1). Both wild- Montre´ al, Que´ bec, Canada H3T 1E2. E-mail: [email protected] type and heterozygous Sam68 mice displayed normal Received 27 September 2006; revised 31 May 2007; accepted 1 June 2007; and comparable ductal outgrowth (Figure 1a, top and published online 9 July 2007 middle panels) consistent with Sam68 þ /À females bearing Sam68 modulates signaling in mammary tumorigenesis S Richard et al 549 Figure 1 Sam68À/À mice display a mammary gland defect. (a) Whole-mount analysis of mammary glands from Sam68 mice is shown (n>4). Scale bar 2 mm and the lymph node (LN) is depicted. (b) Terminal-end buds and number of branchings were counted and expressed as the mean7s.d. of the mean. *P-valueo0.01. (c) Histological examination by hematoxylin/eosin of 6- and 12-week-old mammary glands from Sam68 þ / þ , Sam68 þ /À and Sam68À/À mice. Scale bar, 100 mm. Oncogene Sam68 modulates signaling in mammary tumorigenesis S Richard et al 550 normal litters and lactating normally (data not shown). MMTV-PyMT transgenic as a model to assess the effect In contrast, Sam68À/À mice had a striking defect in the of Sam68 haploinsufficiency in mammary tumor deve- development of the ductal outgrowth observed in 6- lopment and tumor incidence. Sam68À/À mice displayed week-old mice, and this difference was less obvious and an overt mammary defect (Figure 1), and, therefore, partially recovered in 12-week-old mice (Figure 1a, could not be used in these studies. Therefore, Sam68 þ /À lower panels). The 6-week-old Sam68À/À mice had mice were bred with MMTV-PyMT transgenic mice and approximately three times less terminal end buds 6-week-old female offspring palpated twice a week in the compared with Sam68 þ / þ and Sam68 þ /À littermate mice mammary glands for the development of tumors. The (Figure 1b). Adult virgin female mice of 12-week-old animals were killed as soon as one tumor reached mice had fully developed ductal trees; however, the 1.5 cm3 in size and the data expressed using a Kaplan– ductal outgrowth density was lower in whole mounts of Meier analysis. The absence of one allele of Sam68 Sam68À/À mice compared to Sam68 þ / þ and Sam68 þ /À in PyMT/Sam68 þ /À mice (n ¼ 14) delayed tumor deve- mice, as assessed by counting the number of branches in lopment to 122 days as opposed to 80 days observed a given area (Figure 1b). Histological analysis of the in PyMT/Sam68 þ / þ (Figure 3a). The tumor onset in mammary glands showed a normal epithelium with wild-type background was approximately 11 weeks, fewer cross-sections of mammary ducts in the 6-week- consistent with a C57BL6/FVB mice mixed back- old Sam68À/À female mice compared to littermate ground (Cheng et al., 1998). To assess tumor multi- controls or 12-week-old Sam68À/À mice, as predicted plicity, cohorts of PyMT/Sam68 þ / þ (n ¼ 15) and with the reduced ductal outgrowth in 6-week-old PyMT/Sam68 þ /À (n ¼ 10) female mice were analysed. Sam68À/À mice (Figure 1c). We also noted a marked decrease in tumor multiplicity We next investigated the gross morphological analysis in PyMT/Sam68 þ /À mice compared to PyMT/Sam68 þ / þ of the ovaries and uteri derived from 6- and 12-week-old mice, with an average of 2.5 and 4.92 tumors per Sam68 mice. The gross morphology of the uteri from 6- mouse, respectively (Figure 3b). These data indicate that week-old Sam68À/À females appeared atrophic and less Sam68 haploinsufficiency results in both increased developed compared with Sam68 þ / þ and Sam68 þ /À tumor latency and decreased tumor multiplicity in mice; however, this difference was not visible in 12- the MMTV-driven PyMT mice. These findings suggest week-old Sam68À/À mice (Figure 2a). Histological that Sam68 is required for PyMT-induced mammary analysis revealed a normal endometrium with a well- tumorigenesis. organized outer layer of smooth muscle in Sam68 mice (Figure 2b). However, cross-sectioning of the uteri revealed that the uteri of Sam68À/À mice are smaller Src and FAKare activated in PyMT/Sam68 þ /À tumors than those observed in Sam68 þ / þ and Sam68 þ /À mice PyMT-mediated tumorigenesis involves recruitment (Figure 2b). Histologically, no discernable difference is and/or activation of several signaling molecules includ- observed between ovaries from 6- and 12-week-old ing c-Src, phosphatidylinositol 3-kinase (PI-3K), Akt Sam68 mice (Figure 2c). Primary follicles and corpora and Ras (Andrechek and Muller, 2000). As an lutea are present, consistent with the fact that Sam68À/À intracellular target of Src, Sam68 itself may be a female mice are fertile and give birth to reduced litter downstream effector of the PyMT pathway. To deter- sizes (Richard et al., 2005). Taken together, our mine whether the decreased tumorigenicity in PyMT/ observations show that Sam68 deficiency delays the Sam68 þ /À mice is associated with altered expression normal development of the uterus. and/or activation of selected PyMT-coupled signaling molecules, we performed immunoblotting on tumor tissues from PyMT/Sam68 þ / þ and PyMT/Sam68 þ /À Sam68 haploinsufficiency delays mammary tumor onset mice. Tumor extracts from PyMT/Sam68 þ /À mice and multiplicity in PyMT transgenic mice showed B50% decrease in the level of Sam68 expression Mammary tumorigenesis phenotypically similar to human consistent with heterozygosity (Figure 4, top panel).
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