Mice Lacking Dystrophin or α Sarcoglycan Spontaneously Develop Embryonal Rhabdomyosarcoma with Cancer-Associated p53 Mutations and Alternatively Spliced or Mutant Mdm2 Transcripts

Abstract

Altered expression of proteins in the dystrophin-associated glycoprotein complex results in muscular dystrophy and has more recently been implicated in a number of forms of cancer. Here we show that loss of either of two members of this complex , dystrophin in mdx mice or ␣ sarcoglycan in Sgca ؊/؊ mice , results in the spontaneous development of muscle-derived embryonal rhabdomyosarcoma (RMS) after 1 year of age. Many mdx and Sgca ؊/؊ tumors showed increased expression of insulin-like growth factor 2, retinoblastoma protein , and phosphorylated Akt and decreased expression of phosphatase and tensin homolog gene , much as is found in a human RMS. Further , all mdx and Sgca ؊/؊ RMS analyzed had increased expression of p53 and murine double minute (mdm)2 protein and contained missense p53 mutations previously identified in human cancers. The mdx RMS also contained missense mutations in Mdm2 or alternatively spliced Mdm2 transcripts that lacked an exon encoding a portion of the p53-binding domain. No Pax3:Fkhr or Pax7:Fkhr translocation mRNA products were evident in any tumor. Expression of natively glycosylated ␣ dystroglycan and ␣ sarcoglycan was reduced in mdx RMS , whereas dystrophin expression was absent in almost all human RMS , both for embryonal and alveolar RMS subtypes. These studies show that absence of members of the dystrophin-associated glycoprotein complex constitutes a permissive environment for spontaneous development of embryonal RMS associated with mutation of p53 and mutation or altered splicing

Dystrophin is a tumor suppressor in human cancers with myogenic programs

“…The relevance of these findings is supported by reports of spontaneous RMS in DMD -inactivated mdx mice 27–29 . Similarly, reports of RMS in Duchenne muscular dystrophy patients suggest that germline DMD inactivation may predispose to myogenic cancer 30,31 .…”

Rhabdomyosarcomas in Aging A/J Mice

“…Alpha sarcoglycan (dystrophin-associated glycoprotein) ( Sgca ) had one nsSNP it shared with several other strains (not BALB/cJ) (7 targeted mutants, all with muscular dystrophy, listed in Mouse Genome Informatics (http://www.informatics.jax.org/)), Myl1 had a lost stop codon it shared with several other strains (not BALB/cJ) (3 targeted mutants, one with muscle defects, one with growth defects; MGI), Abra had 4 nsSNPs it shared with several other strains (not BALB/cJ) (1 targeted mutant with cardiovascular defects; MGI), Titin ( Ttn ) had one nsSNP in A/J that it did not share with any other strain (6 spontaneous, chemically-induced, and targeted mutants, all with muscular dystrophy/defects; MGI), and the potassium inwardly rectifying channel, subfamily J, member 12 ( Kcnj12 ) had 3 nsSNPs all marked as having multiple consequences that it shared with several other strains (not BALB/cJ; no evidence of skeletal muscle problems with 2 targeted mutants; MGI). As mentioned previously, B6.129S6- Sgca tm2Kcam / J null mice also develop random RSCs, despite being on a non-permissible background (C57BL/6J) [14]. Therefore, these genes ( Myl1, Abra, Sgca, Ttn, Kcnj12 ) and proteins will be the focus of future investigations.…”

Probing for a deeper understanding of rhabdomyosarcoma: insights from complementary model systems

“…89). For example, Dmd 90,91 and dysferlin ( Dysf ) 92–94 mutations in mice result in RMS, although at higher rates than those seen in humans; this is likely to be due to the fact that the milder dystrophic phenotypes that occur in mice allow for a comparatively longer window for tumorigenesis. Recently, somatic deletions in DMD have been identified in sporadic human myogenic tumours, including ERMS 95 .…”