The metastasis-associated gene MTA1 is upregulated in advanced ovarian cancer, represses ERbeta, and enhances expression of oncogenic cytokine GRO.

The metastasis-associated genes MTA1 and MTA3 are transcriptional repressors with potential effects on cancer. We analyzed the expression of MTA1, MTA3, ERalpha, ERbeta and E-cadherin in a total of 115 paraffin-embedded ovarian cancer tissues with respect to cancer staging and FIGO grading. Expression of MTA1, but not that of MTA3, was found to be significantly enhanced in ovarian cancer tissues with advanced cancer stages and higher FIGO grading, indicating an important role of MTA1 in the progression of ovarian cancer. To get further insights into the function of MTA1 in ovarian cancer, MTA1-overexpressing cancer cell clones were generated. In vitro, overexpression of exogenous MTA1 in OVCAR-3 cells had no effect on cell proliferation but enhanced the ability of anchorage-independent growth in soft agar colony formation assays. MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG. MTA1 further reduced ERbeta expression in vitro and inversely correlated with ERbeta expression in vivo. Screening for the expression of angiogenic cytokines expressed by ovarian cancer cells revealed MTA1-mediated upregulation of the oncogenic and angiogenic cytokine GRO (growth-regulated oncogene, CXCL1). Thus, in ovarian cancer, MTA1 expression directly and indirectly regulates the expression of several cancer-promoting as well as metastasis-facilitating factors, indicating an important role for MTA1 expression during ovarian cancer progression.