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Rho GTPases have multiple roles in cancer. We are working to characterise the novel Rho GTPase RhoBTB2/DBC2, which has been reported to be a tumour suppressor in breast cancer.
We used siRNA to mimic the loss of RhoBTB2 expression in breast cancer and then microarray analysis to identify the gene targets of RhoBTB2.
Screening identified the homeostatic chemokine CXCL14/BRAK as a target of RhoBTB2. CXCL14 is highly expressed by normal epithelial cells; however, its expression is downregulated in a wide range of carcinomas. We found that expression of both RhoBTB2 and the closely related RhoBTB1 gene are required for CXCL14 expression in epithelial cells. Loss of RhoBTB2 expression in cancer correlated with loss of CXCL14, and re-expression of RhoBTB2 in cancer cells restored CXCL14 expression.
The high incidence of downregulation of RhoBTB2 (ca. 60%) and RhoBTB1 (ca. 50%) found across a wide range of carcinomas is sufficient to explain the observed frequency of downregulation of CXCL14. We propose that downregulation of RhoBTB1/2 represents the causative mechanism for altered CXCL14 expression in cancer cells. Previous work has shown that CXCL14 expression is lost from mammary epithelial cells in ductal carcinoma in situ, but is upregulated in the surrounding myoepithelial cells. This is suggestive of an autocrine to paracrine switch. In keeping with this, we find that exogenous CXCL14 disrupts the organisation of mammary cell acini grown in three-dimensional culture. Similar switching in CXCL14 production from epithelium to stroma has been reported in prostate and oral carcinoma. We are currently investigating the contribution of CXCL14 on invasive behaviour.