Abstract P4-08-08: HOXC10, a homeobox protein overexpressed in breast cancer, modulates the response to chemotherapy treatment.

Abstract

Abstract Background: Breast cancer is the second leading cause of cancer deaths in women worldwide. Although chemotherapy is effective, resistance to drugs develops over time and can account for treatment failure in over 90% of metastatic breast cancer patients. HOX genes are homeobox-containing transcription factors well-known for their role in morphogenesis. and during carcinogenesis and metastasis. The goal of this study is to understand the role of HOXC10 in breast cancer and mainly in response to chemotherapy. Methods: Using a tiling array of all four HOX clusters in a panel of primary and metastatic breast cancer tissues, we identified HOXC10 as being among the highly overexpressed genes in breast cancer. Then using a panel of cell lines that either stably overexpress exogenous HOXC10 or cell lines with stably downregulated endogenous HOXC10 (mediated by shRNA), we investigated the role of HOXC10 in proliferation, response to chemotherapy treatment and repair of DNA damage. Results: HOXC10 is overexpressed in 67% of primary breast tumors (n = 31), in 82% of the metastatic tissues (n = 49) and in most breast cancer cell lines (n = 48). In vitro and in vivo investigation confirmed that HOXC10 plays an oncogenic role in breast cancer. Further, knockdown of HOXC10 in a panel of breast cancer cell lines slowed their proliferation and arrested them at the G1 phase, by inactivating the RB/E2F pathway, decreasing the number of new origins and eventually reducing the polyploidy population. Cell survival assays after different chemotherapeutic drug treatment showed that overexpression of the exogenous HOXC10 in MCF10A led to less susceptibility to most drugs. This was partially due to a protection from apoptosis by upregulating and activating the anti-apoptotic machinery such as the NF-kb pathway. Further investigation revealed the involvement of HOXC10 in DNA repair (and not initial response), especially after DNA crosslink damage. Interestingly, the binding of HOXC10 to CDK7 in a region outside its homeodomain activates CDK7 activity towards RNA polymerase II mainly in response to DNA damage. Since HOX genes are difficult to target therapeutically, one potential approach to overcome chemoresistance in HOXC10 overexpressing cells is by including CDK7 inhibitors (already in clinical trials). All these results were confirmed in the SUM159 model which stably expresses a HOXC10-shRNA. Finally, HOXC10 was found to be significantly overexpressed in MCF7 isogenic cell lines gradually selected to be resistant to some chemotherapeutic drugs. By knocking down HOXC10 in these sublines, resistance to the drug was reduced. Further, SUM159 and MDAMD231 xenografts that were treated with chemotherapy over weeks and that show partial to no response tend to have a higher expression of HOXC10. Conclusion: This study shows that HOXC10, a homeobox protein previously shown to be regulated during the cell cycle and to have a positive effect on proliferation, is overexpressed in the majority of breast cancers. This upregulation may have clinical implications since cells with higher expression of HOXC10 tend to have more genomic instability and activation of anti-apoptotic and DNA repair pathways, which eventually modulate the response to some chemotherapy drugs. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-08-08.