CD44 ISOFORMS CORRELATE WITH CELLULAR-DIFFERENTIATION BUT NOT WITH PROGNOSIS IN HUMAN BREAST-CANCER

CD44 is a transmembrane glycoprotein occurring in several isoforms wit h different extracellular regions. The various transcripts are encoded by one gene locus containing 20 exons, of which at least 10 can be al ternatively spliced in nascent RNA. Isoforms encoded by the variant ex ons (termed CD44v) are highly restricted in their distribution in non malignant tissue as opposed to the standard form of CD44 (CD44s) abund ant in many tissues. Specific variant isoforms containing exon 6v have been shown to render nonmetastatic rat tumor cells metastatic. Based on the prominent role in rat metastasis formation, CD44v isoforms were suggested to be involved in human tumor progression, Correlations bet ween prognosis and expression of CD44 have been reported for gastric a nd colon carcinoma, for non-Hodgkin's lymphoma, and recently for breas t carcinoma. We evaluated the expression of CD44 isoforms in node-posi tive (n = 119) and node-negative (n = 108) cases of breast carcinoma b y immunohistochemistry using CD44v exon-specific mAbs. In a subset of 43 cases of high risk patients, reverse transcription-PCR was used to determine the exon composition of the transcripts, Protein and RNA exp ression data mere probed statistically for their correlation to surviv al of the patients and clinical risk factors. In contrast to recently published data (M. Kaufmann et at, Lancet, 345: 615-619, 1995), in our cohort disease-free and overall survival data did not indicate signif icant correlations with the expression of the analyzed isoforms in uni variate and multivariate analyses. Comparison of CD44 protein expressi on with established clinical risk factors for survival such as tumor s ize (pT(1) + pT(2)) and histological grading revealed correlations wit h the presence of CD44s (p = 0.02 and P = 0.03, respectively) and CD44 -9v (P = 0.05 for histological grading), Carcinoma tissues with elevat ed estrogen and progesterone receptor levels showed positive correlati on with CD44-6v (P = 0.001), white a trend for significant coexpressio n of CD44s and CD44-9v isoforms was observed in estrogen receptor-posi tive tissues (P = 0.08 and 0.06, respectively). In breast cancer, CD44 s, CD44-9v, and CD44-6v are apparently markers for cellular differenti ation but not for tumor progression. Our data suggest that steroid hor mone receptors may be associated with the in vivo expression of CD44-6 v-containing isoforms in human mammary carcinoma.