Relaxation of onconeural gene transcription control in NRSF deficient primary invasive breast and ovarian gynecological tumors

Negative regulation of many neuronal genes is mediated by the neuron-restrictive silencer factor (NRSF or REST), which binds to a neuron-restrictive silencer element (NRSE) and thereby represses transcription of neuronal genes in non-neuronal cells. The expression of neuronal cell markers in malignant tumors, like small cell lung cancer (SCLC), primary invasive breast cancer, and more rarely in ovarian cancer frequently correlates with paraneoplastic disorders, but also with a higher invasiveness and a poorer prognosis. Recently, NRSF has been postulated as a tumor suppressor gene in the development of cancer.

Our previous publication (Neumann et al., 2004) examined different SCLC tumor cell lines for the expression of NRSF, neuronal glycine receptor subunits (e.g. GlyR α1), the L1 cell adhesion molecule (L1CAM) and the neural cell adhesion molecule (NCAM) genes. In two SCLC cell lines a lack of NRSF transcripts correlated with the up-regulation of GlyR α1 and L1CAM and NCAM. In the present investigation we have now extended our analysis to examine the levels of NRSF, L1CAM and NCAM transcripts in primary tissues and cell lines of breast and ovarian tumors compared to control breast and ovarian tissues. In contrast to control tissues, RT-PCR results for both breast and ovarian carcinomas demonstrated lower levels of NRSF, whereas L1CAM or NCAM expression were elevated. Importantly, the lowest NRSF expression levels appeared to associate with Her2/neu-positive and ER-negative, PR-negative breast carcinomas. We are examining NRSF, L1CAM and NCAM gene expression levels using both semi- and absolute quantitative Realtime PCR in a larger tumor collective. In addition, we are performing cell culture experiments to address the putative role of these genes in tumor invasiveness.

We propose that the lack of NRSF resulting in up regulation of L1CAM and NCAM may be significant for the development of carcinogenesis by influencing tumor invasion and migration.