c-FOS suppresses ovarian cancer progression by changing adhesion

Ovarian carcinoma is mostly diagnosed in advanced stages when intraperitoneal metastasis has already taken place. Up to now, therapy is based on optimal surgical tumour reduction (debulking) followed by platin-based combination chemotherapy. In spite of intensive research, there are no established molecular prognostic or predictive markers for this cancer type, and new molecular targets for an individualised therapy are urgently needed. In search for new markers, we found that against expectation, high c-FOS protein expression in tumour tissue was associated with a significantly prolonged recurrence-free and overall survival and had an independent favourable impact on tumour progression (Mahner et al, 2008). c-FOS encodes a transcription factor of the activating protein-1 (AP-1) family which, after dimerisation with one of the Jun proteins, participates in regulation of a variety of genes, partly involved in tumour growth and progression (Durchdewald et al, 2009). First identified because of its homology to the retroviral oncogene v-fos which induces murine osteogenic sarcomas, human c-FOS causes osteosarcomas in transgenic mice (Ruther et al, 1989) and is able to transform rodent fibroblasts (Miller et al, 1984). In humans, an oncogenic function of c-FOS was proposed in tumours of the bone (Gamberi et al, 1998), skin (Guinea-Viniegra et al, 2012), brain (Silvestre et al, 2010) and lung (Volm et al, 2002). Yet, in murine mammary carcinoma cells c-FOS was found only in non-metastatic cells, whereas Fra-1 and Fra-2 dominated in metastatic descendants (Kustikova et al, 1998). In the last years, the idea of c-FOS as a Janus-type regulator (Durchdewald et al, 2009) with possible tumour-suppressor qualities emerged. c-FOS inhibits proliferation of neoplastic hepatocytes (Mikula et al, 2003), is decreased in thyroid tumours (Liu et al, 1999) and has a positive prognostic impact in gastric cancer (Jin et al, 2007). In ovarian cancer (OvCa), high c-FOS expression correlated with a well-differentiated phenotype (Meinhold-Heerlein et al, 2005), is reduced in metastases compared with primary tumours (Hein et al, 2009), and an independent favourable prognostic marker (Mahner et al, 2008). In order to further investigate the tumour-suppressor effect of c-FOS in ovarian carcinomas, we performed functional assays and in vivo tests using OvCa cells with stable c-FOS overexpression. Our results point to a strong influence of c-FOS on cell adhesion and provide an explanation for the favourable prognostic impact of this protein in clinical OvCa.