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

描述（由申请人提供）：许多研究得出结论，与非AA女性相比，绝经前非洲裔美国人（AA）女性患雌激素受体（ER）阴性乳腺癌的比例显著较高。最近已经清楚的是，许多ER阴性肿瘤也缺乏孕酮受体（PR）和HER 2表达-这些肿瘤被称为“三阴性癌症”（TNBC）。由于AA女性中TNBC乳腺癌的比例（55%）是白色女性肿瘤中发现的比例（23%）的两倍多，因此TNBC的难治性现在被认为是年轻AA和非AA乳腺癌患者结果之间健康差异的一个重要组成部分。因此，即使在对社会经济因素进行调整后-包括获得筛查和适当的护理-改善TNBC的治疗可能会改善全球有色人种妇女的健康差距。在可能导致TNBC化疗耐药性的因素中，SGK 1的过表达是我们实验室发现的PI 3-K活化下游的非常有效的抗凋亡激酶，其在约30%的TNBC中过表达，我们假设其有助于化疗耐药性。在该提案中，我们提出增加的SGK 1表达水平有助于TNBC对常规化疗（多柔比星和紫杉醇）以及新型疗法（例如Hsp 90抑制剂）的治疗抗性。为了检验这一假设，我们提出了三个具体目标：1）确定SGK 1过表达是否抑制TNBC细胞系中紫杉醇或阿霉素诱导的细胞凋亡; 2）检查预测的SGK 1介导的对TNBC中Hsp 90介导的细胞凋亡的抗性的机制，以及3）确定SGK 1表达是否有助于TNBC对常规化疗和/或Hsp 90抑制剂的体内抗性。该项目的完成将增加我们对SGK 1生物学在TNBC传统和新疗法的治疗抗性中的作用的了解，为PI 3 K/SGK 1抑制剂在这些癌症中的合理使用铺平道路，这些癌症不成比例地影响年轻AA女性。 公共卫生相关性：三阴性乳腺癌（TNBC）是乳腺癌的一种亚型，不成比例地影响年轻AA女性。由于TNBC的复发增长速度相对较快，并且常规化疗之外的治疗选择有限，因此必须确定TNBC化疗耐药性的机制。我们建议研究SGK 1的作用，SGK 1是一种由PI 3-K途径磷酸化和激活的抗凋亡激酶，其可能在TNBC对化疗的耐药性中发挥作用。在过度表达这种蛋白质的肿瘤中靶向SGK 1可能会克服各种治疗对细胞凋亡的抵抗。

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.