Feline STK gene expression in mammary carcinomas

Abstract

The human RON and its mouse homologue stk are members of the MET family of tyrosine kinase receptors. We have previously shown that the RON gene is over-expressed in human breast carcinomas. As cat mammary tumours have been proposed as a suitable model for aggressive human breast cancer, we identi®ed the feline stk gene and studied its expression in cat mammary cancer. Feline stk sequences were found highly homologous to the stk and RON gene exons that encode the juxtamembrane and transmembrane domains of the stk and RON receptors. Feline stk-speci®c transcript was detected by RT ± PCR in cat lung and in 7/8 feline mammary carcinomas and a synchronous skin metastasis examined. Western blot and immunohistochemical analyses were carried out with an antibody that recognized both the human RON and mouse stk receptors. This antibody speci®cally detected a 135 Kd feline protein and stained 10/34 mammary carcinoma archival samples. These data show that the pattern of expression and distribution of the stk protein in feline mammary cancer could be superimposed on that of the RON receptor in human breast cancer and suggest that these feline tumours are a suitable model to test innovative approaches to therapy of aggressive human breast carcinomas. Oncogene (2002) 21, 1785 ± 1790. DOI: 10.1038/sj/ onc/1205221Keywords: tyrosine kinase receptors; mammary carcinomas; companion animals tumours Spontaneous tumours in companion animals oer a unique opportunity as models of human cancer. The relatively high incidence of some cancers, large body size and shorter overall lifespan are factors that contribute to the advantage of these models. Above all, in most cases histopathology and comparable responses to the cytotoxic agents make tumours in companion animals useful to test new therapeutic approaches like new chemotherapeutic regimens, gene therapy and biological modi®cations. However, to date only fragmentary information is available on molecular alterations and biological behaviour of companion animal tumours.In cats, mammary cancer is a frequent neoplasm (%10% all cases, 17% for females), the most common after lympho-hematopoietic and skin tumours. On the basis of age incidence, histopathology and pattern of metastasis, feline mammary cancer (FMC) could be a good comparative model of human breast cancer (for a review see Weijer et al., 1972). In particular, the lack of estrogen dependency in most tumours (De las Mulas et al., 2000) may indicate that FMC is a suitable animal model for human hormonal-unresponsive breast cancer. The ®nding of over-expression and ampli®cation of cyclin A (Murakami et al., 2000a) and p53 nuclear accumulation (Murakami et al., 2000b) suggests also a similar tumorigenesis.Over-expression of tyrosine kinase oncogenes has been reported in many carcinomas (for a review see Kolibaba and Druker, 1997). In vitro and in vivo studies suggested that among these receptors, those of the MET family might be speci®cally involved in the activation of the tyrosine kinase cascade that stimulates invasive properties...

Altered Exon Usage in the Juxtamembrane Domain of Mouse and Human RON Regulates Receptor Activity and Signaling Specificity

“…Amino acid sequence alignment of hRON and mRON revealed that mRON has a 27-amino acid deletion in the relatively diverse juxtamembrane region when compared with mRON (Figs. 5 and 7A) caused by exclusion of a potential exon in the mRON cDNA sequence, which has previously been reported by other investigators (19). Genomic sequence comparison showed that the sequence of the juxtamembrane domainencoding exon exists in the major transcripts of all other known RON orthologs including human, rat, feline, and chicken, and no alternative splicing events in this region have been reported thus far.…”

“…However, overexpression of wild type mouse RON, but not human RON, has been reported to induce the transformation of NIH 3T3 cells in vitro (18). We and others have observed that an exon encoding part of the juxtamembrane domain in major transcripts of all other known RON orthologs is missing in the murine RON transcript (19). Here we have shown that the resultant juxtamembrane domain in murine RON induces enhanced receptor phos-phorylation, activation of the MAP kinase cascade, and association of RON with c-Src when compared with human RON.…”

Oncogenic Signaling Pathways Activated by RON Receptor Tyrosine Kinase

“…The detection of RON expression in feline mammary carcinomas supports RON involvement in breast cancer progression. Mammary cancer represents 17 % of all carcinomas in female cats [20]. Investigation of the feline RON gene revealed a high homology to the human RON.…”

Met‐Related Receptor Tyrosine Kinase Ron in Tumor Growth and Metastasis

“…HGFL is able to induce Ron activation in T47D cells, and stimulation of Ron receptor in ZR 75.1 cells causes increased cell proliferation, invasion and about a 12-fold increase in migration (Gaudino et al, 1994;(Maggiora et al, 1998). Interestingly, a feline form of Ron was found to be overexpressed in about 33% of archival feline mammary carcinoma samples tested (De Maria et al, 2002). Mouse models have also demonstrated an important role for Ron in mammary tumorigenesis Zinser et al, 2006).…”