Abstract
Despite the lack of an increased rate of breast cancer occurrence among African American women, African American women suffer greater mortality due to breast cancer as compared with other ethnic groups. Recent studies suggest that the increase in mortality is likely multifactorial, however the elevated occurrence of triple negative (ER-/PR-/HER2-) breast cancer may be a key factor in decrease survival among African American women. Since the lack of ER and HER2 make these patients ineligible for hormonal therapy or Her2 targeted therapies such as trastuzumab, patients are often relegated to cytotoxic chemotherapeutic strategies. As such, it is imperative to identify therapeutic targets which can be exploited to design highly selective, less toxic regimens which are effective in treating triple negative breast cancer. The NR4A (NR4A1, NR4A2, and NR4A3) orphan nuclear receptors have the potential to serve as distinct, specific pharmacological targets which can directly affect apoptosis in triple negative breast cancer cells. Breast tumor microarrays demonstrate that NR4A2 is highly expressed in the nucleus of normal, but not malignant breast epithelial cells. shRNA-mediated silencing of NR4A2 in triple negative breast cancer cells leads to increased proliferation in vitro and in breast cancer xenograft models. In vitro studies also revealed that shRNA silencing of NR4A2 expresssion mediated partial resistance to doxorubicin, while overexpression of NR4A2 leads to cell cycle arrest. Additionally, gene expression arrays show that overexpression of NR4A2 induces expression of angiogenic factors, as well as causes suppression of markers associated epithelial-mesenchymal transition. Taken together, these studies suggest that NR4A2 is a viable pharmacological target in triple negative breast cancer. Targeting triple negative breast cancer may prove an effective means to address the disparity in survival rates of African American women as compared to other ethnicities.
Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B60.
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