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

SGK1 在三阴性乳腺癌治疗耐药中的作用

• 批准号: 7880513
• 负责人: Suzanne Daniela Conzen
• 金额: $ 18.53万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7880513
• 关键词: 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin; Address; Affect; African; African American; Age; Apoptosis; Apoptotic; Basic Cancer Research; Biological; Biological Assay; Biology; Breast Cancer Cell; Cancer Patient; Cancer cell line; Caring; Catalytic Domain; Cell Line; Cell Survival; Characteristics; Chemotherapy-Oncologic Procedure; Clinical; Clinical Trials; Color; Correlative Study; Data; Diagnostic Neoplasm Staging; Doxorubicin; Ductal Epithelium; ERBB2 gene; Estrogen Antagonists; Estrogen Receptors; Estrogen receptor negative; Gene Expression; Genetic; Glucocorticoids; Growth; Health Services Accessibility; Human; Immunohistochemistry; In Vitro; Knowledge; Laboratories; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Molecular; Molecular Profiling; Nature; Neoplasm Metastasis; Nucleic Acid Regulatory Sequences; Outcome; Paclitaxel; Pathway interactions; Phase; Phosphotransferases; Play; Predisposition; Premenopause; Progesterone Receptors; Proteins; Refractory; Relapse; Relative (related person); Resistance; Role; Screening procedure; Serum; Serum Proteins; Signal Transduction; Socioeconomic Factors; Stratum Basale; Study of serum; Testing; Therapeutic; Tumor Biology; Withdrawal; Woman; Xenograft procedure; anti-cancer therapeutic; antiangiogenesis therapy; base; cancer health disparity; chemotherapy; clinical efficacy; conventional therapy; cytotoxicity; experience; health disparity; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; mortality; novel; overexpression; pre-clinical; public health relevance; receptor; resistance mechanism; response; therapy resistant; triple-negative invasive breast carcinoma; tumor; ultraviolet irradiation

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.

描述（由申请人提供）：大量研究得出结论，与非 AA 女性相比，绝经前非裔美国 (AA) 女性患雌激素受体 (ER) 阴性乳腺癌的比例明显更高。最近，人们已经清楚许多 ER 阴性肿瘤也缺乏孕激素受体 (PR) 和 HER2 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%) 是白人女性肿瘤 (23%) 的两倍多，因此 TNBC 的难治性现在被认为是年轻 AA 之间健康差距的一个重要组成部分。和非 AA 乳腺癌患者的结果。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 的治疗也可能会改善全球有色人种女性的健康差距。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，我们的实验室发现它在约 30% 的 TNBC 中过度表达，我们假设它会导致化疗耐药。在该提案中，我们提出SGK1表达水平的增加有助于TNBC对传统化疗（阿霉素和紫杉醇）以及新疗法（例如Hsp90抑制剂）的治疗耐药。为了检验这一假设，我们提出了三个具体目标：1) 确定 SGK1 过表达是否会抑制 TNBC 细胞系中紫杉醇或多柔比星诱导的细胞凋亡； 2) 检查预测的 SGK1 介导的对 TNBC 中 Hsp90 抑制剂诱导的细胞凋亡的抵抗机制，以及 3) 确定 SGK1 表达是否有助于 TNBC 对常规化疗和/或 Hsp90 抑制剂的体内抵抗。该项目的完成将增加我们对 SGK1 生物学在 TNBC 传统疗法和新疗法耐药性中的作用的了解，为合理使用 PI3K/SGK1 抑制剂治疗这些对年轻 AA 女性造成不成比例影响的癌症铺平道路。 公共健康相关性：三阴性乳腺癌 (TNBC) 是乳腺癌的一种亚型，对年轻 AA 女性的影响尤为严重。由于 TNBC 的复发率相对较快，并且传统化疗以​​外的治疗选择有限，因此必须确定 TNBC 化疗耐药的机制。我们建议研究 SGK1（一种由 PI3-K 通路磷酸化和激活的抗凋亡激酶）的作用，因为它可能在 TNBC 化疗耐药中发挥作用。在过度表达该蛋白的肿瘤中靶向 SGK1 可能会克服多种治疗对细胞凋亡的抵抗。