A twisted kiss: in vitro and in vivo evidence of genetic variation and suppressed transcription of the metastasis-suppressor gene KiSS1 in early breast cancer

Rok, strany: 2010, 47 - 54

KiSS-1 is a metastasis suppressor gene, its inactivation linked to advanced tumor stage and dismal prognosis. We studied its mutational status , transcription and protein expression in human cancer cell lines and patients with early breast cancer.<br />Tumor tissue DNA and messenger RNA (mRNA) of KiSS1 exons III and IV from the human cancer cell lines Hela, Jurkat, A549, W138t, MCF-7 and from formalin-fixed resected breast adenocarcinomas from 50 women were analysed by means of PCR-SSCP, RT-PCR and sequencing. Tumor tissue was stained for KiSS1 protein expression by means of the streptavidin-biotin complex immunoperoxidase assay. Presence of KiSS1 mutation, mRNA levels and protein staining were examined for correlations with patient/tumor characteristics. <br />A transversion in exon IVa replacing cytosine with guanine was identified 242 base pairs from the translation start site (242C>G) in the cell lines MCF-7, A549 and in 5/50 tumors (10%), resulting in substitution of proline by arginine (P81R) and alteration of the protein tertiary structure. As the substitution was present in germ-line DNA in 3/5 breast cancer patients harbouring the polymorphism in their tumor, the incidence of tumour-specific somatic mutation was 4% among the 50 patiens with early breast cancer. Although the P81R substitution was associated with reduced KiSS1 protein immunoreactivity (56% in wild-type tumors versus 20% in KiSS1-variant tumours) and with axillary nodal involvement (55% in wild-type versus 80% in KiSS1-variant tumors), the correlations did not reach statistical significance. KiSS1 mRNA was detected in only 15/48 tumours (31%) and showed no correlation with mutation or protein expression. Twenty-six tumors stained for KiSS1 protein, in contrast to the universal strong staining seen in normal breast parenchyma and placental tissues. At a median follow-up of 38 months, relapses occurred in 20% of women with non wild-type tumors versus 13% of women with wild-type KiSS1 tumors (p=0.7). Presence of KiSS1 mutation, mRNA levels and protein expression did not have prognostic significance for relapse-free survival.<br />In conclusion, altered nucleotide sequence and repression of transcription are two potential mechanisms of suppression of the anti-metastatic effects of KiSS1 in early breast cancer: Confirmation in larger cohorts and study of functional effects of the 242C>G exon IVa mutation are warranted. Keywords: KiSS1, metastasis-suppressor gene, breast cancer, mutation, transcription.

ISO 690:

Pentheroudakis, G., Kostadima, L., Dova, L., Georgiou, I., Tzavaras, T., Vartholomatos, G., Wirtz, R., Fountzilas, G., Malamou-Mitsi, V., Pavlidis, N. 2010. A twisted kiss: in vitro and in vivo evidence of genetic variation and suppressed transcription of the metastasis-suppressor gene KiSS1 in early breast cancer. In NEOPLASMA, vol. 57, no.1, pp. 47-54. 0028-2685.

APA:

Pentheroudakis, G., Kostadima, L., Dova, L., Georgiou, I., Tzavaras, T., Vartholomatos, G., Wirtz, R., Fountzilas, G., Malamou-Mitsi, V., Pavlidis, N. (2010). A twisted kiss: in vitro and in vivo evidence of genetic variation and suppressed transcription of the metastasis-suppressor gene KiSS1 in early breast cancer. NEOPLASMA, 57(1), 47-54. 0028-2685.