Numerous studies have concluded that pre-menopausal African-American (AA) women have a significantly higher proportion of estrogen receptor (ER)-negative breast cancers compared to non-AA women. More recently it has become clear that many ER-negative tumors also lack progesterone receptor (PR) and HER2 expression- these tumors are termed "triple negative cancers" (TNBC). Because the proportion of TNBC breast cancer in AA women (55%) is more than double than that found in tumors of white women (23%), the refractory nature of TNBC is now recognized as one important component to the health disparity between young AA and non-AA breast cancer patient outcome. Thus, even after adjustments for socioeconomic factors- including access to screening and appropriate care- improving treatment of TNBC will likely improve the health disparity observed in women of color worldwide. Among the factors that might contribute to chemoresistance of TNBC is overexpression of SGK1, a very potent anti-apoptotic kinase downstream of PI3-K activation that our laboratory discovered is overexpressed in about 30% of TNBC and which we hypothesize contributes to chemo-resistance. In this proposal, we propose that increased SGK1 expression levels contribute to therapeutic resistance of TNBC to conventional chemotherapy (doxorubicin and paclitaxel) as well as novel therapies (e.g. Hsp90 inhibitors). To test this hypothesis we propose three specific aims: 1) To determine whether SGK1 overexpression inhibits paclitaxel or doxorubicin-induced apoptosis in TNBC cell lines;2) to examine the mechanisms of predicted SGK1-mediated resistance to Hsp90 inhibitor-induced apoptosis in TNBC, and 3) to determine whether SGK1 expression contributes to in vivo resistance of TNBC to conventional chemotherapy and/or Hsp90 inhibitors. Completion of this project will increase our knowledge of the role of SGK1 biology in therapeutic resistance to both traditional and new therapies for TNBC, paving the way for rationale use of PI3K/SGK1 inhibitors in these cancers that disproportionately affect young AA women.

PUBLIC HEALTH RELEVANCE: Triple negative breast cancer (TNBC) is a subtype of breast cancer that disproportionately affects young AA women. Due to TNBC's relatively rapid rate of growth in relapse and limited treatment options beyond conventional chemotherapy, mechanisms of TNBC chemoresistance must be identified. We propose to study the role of SGK1, an anti-apoptotic kinase that is phosphorylated and activated by the PI3-K pathway, for its likely role in TNBC resistance to chemotherapy. Targeting SGK1 in tumors that overexpress this protein is likely to overcome resistance to apoptosis from a variety of treatments.

R21CA149472

2010-09-30

2013-08-31