The role of SGK1 in triple-negative breast cancer resistance to treatment

描述（由申请人提供）：大量研究得出结论，绝经前非裔美国人（AA）女性患雌激素受体（ER）阴性乳腺癌的比例明显高于非AA女性。最近，人们发现许多er阴性肿瘤也缺乏孕激素受体（PR）和HER2的表达——这些肿瘤被称为“三阴性癌症”（TNBC）。由于AA女性TNBC乳腺癌的比例（55%）是白人女性的两倍多（23%），TNBC的难治性现在被认为是年轻AA和非AA乳腺癌患者预后差异的一个重要组成部分。因此，即使在调整了社会经济因素之后——包括获得筛查和适当护理的机会——改善TNBC的治疗可能会改善在世界各地有色人种妇女中观察到的健康差距。可能导致TNBC化疗耐药的因素之一是SGK1的过度表达，SGK1是PI3-K激活下游的一种非常有效的抗凋亡激酶，我们的实验室发现在约30%的TNBC中过度表达，我们假设这有助于化疗耐药。在本提案中，我们提出SGK1表达水平的增加有助于TNBC对常规化疗（阿霉素和紫杉醇）以及新疗法（如Hsp90抑制剂）的治疗抗性。为了验证这一假设，我们提出了三个具体目标：1)确定SGK1过表达是否抑制紫杉醇或阿霉素诱导的TNBC细胞系凋亡；2)研究SGK1介导的TNBC对Hsp90抑制剂诱导的凋亡的耐药机制；3)确定SGK1的表达是否有助于TNBC对常规化疗和/或Hsp90抑制剂的体内耐药。该项目的完成将增加我们对SGK1生物学在TNBC传统和新疗法治疗耐药中的作用的认识，为PI3K/SGK1抑制剂在这些不成比例影响年轻AA女性的癌症中的合理使用铺平道路。

DESCRIPTION (provided by applicant): 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.