Racial Disparities in Breast Cancer and the role of micro-RNAs

描述（由申请人提供）：非洲裔美国人（AA）和高加索人（CA）女性之间的乳腺癌结局存在种族差异。例如，AA女性乳腺癌的死亡率可能是CA的三倍，尽管AA女性的发病率较低（1）。与CA女性相比，AA女性在更早的年龄发展三阴性乳腺癌（TNBC），更经常被诊断为晚期，可能经历转移并且通常对治疗无反应（1，2）。尽管一些患者对化疗有反应，但最初，化疗后1至3年内肿瘤复发，5年内死亡率较高（3）。我们的研究小组和其他人已经报道了癌症干细胞样细胞（CSC或肿瘤起始细胞），其特征在于它们的自我更新和对导致肿瘤复发和转移的治疗的抗性，与其他类型的乳腺癌相比，在TNBC女性中特别丰富（4，5）。我们还观察到，与源自CA TNBC患者的MDA-MB-231和BT549细胞系中的那些CSC相比，源自AA TNBC患者的CRL-2335和MDA-MB 468细胞系中分离的CSC（i）显示出显著更长的存活和形成乳腺球的能力（ii）在用顺铂加肿瘤坏死因子（TNF）相关的凋亡诱导配体（TRAIL）处理后，与在源自CA TNBC患者的MDA-MB-231和BT549细胞系中观察到的那些相比，在CSC更新中起主要作用的Wnt受体之一（也是miR-100的靶标）FZD 8表现出miR-100和miR-23 b的表达降低和FZD 8的显著增加。因此，我们假设癌症干细胞（CSC）自我更新的差异促成了TNBC中的种族差异。为了检验我们的假设，我们有两个具体的目标：目标1：确定与高加索妇女相比，非洲裔美国妇女中CSC在TNBC中的作用。目标二：开发一种新的肿瘤模型，以解决microRNA（miR-100和miR-23 b）在CSC自我更新，肿瘤进展和体内治疗中的作用。成功完成拟议的研究将深入了解CSC的分子生物学及其在AA和CA TNBC患者之间种族差异中的作用（如果有的话），并为有效治疗提供消除CSC的新靶点。

DESCRIPTION (provided by applicant): There is a racial disparity in the breast cancer outcomes between African-American (AA) and Caucasian (CA) women. For example, mortality rates for breast cancer in AA women can be three times higher than for CA, even though the incidence is lower in AA women (1). AA women develop triple-negative breast cancer (TNBC) at earlier age, more often diagnosed with advanced stage, likely to experience metastasis and often unresponsive to treatment compared to CA women (1, 2). Although some patients respond to chemotherapy, initially, tumor recurrence within 1 to 3 years post chemotherapy with high incidence of mortality occurring by 5 years (3). Our research group and others have reported that cancer stem-like cells (CSCs or tumor initiating cells), which are characterized by their self-renewal and resistance to therapy leading to tumor recurrence and metastasis, are particularly abundant in women with TNBC compared to those with other types of breast cancer (4, 5). We have also observed that isolated CSCs in CRL-2335 and MDA-MB468 cell lines derived from AA TNBC patients (i) showed significantly longer survival and the ability to form mammospheres compared to those CSCs in MDA-MB-231 and BT549 cell lines derived from CA TNBC patients (ii) after treatment with cisplatin plus tumor-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), exhibited decreased expression of miR-100 and miR-23b and significant increase in FZD8, one of the Wnt receptors (also a target for miR-100) which plays a major role in CSC renewal, as compared to those seen in MDA-MB-231 and BT549 cell lines derived from CA TNBC patients. Hence, we hypothesized that differences in the self- renewal of cancer stem cells (CSCs) contributes to the racial disparities in TNBC. In order to test our hypothesis, we have two specific aims: Aim 1: Determine the role of CSCs in TNBC in African-American women compared to Caucasian women. Aim 2: Develop a new tumor model to address the role of microRNAs (miR-100 and miR-23b) in CSCs self- renewal, tumor progression and treatment in vivo. Successful completion of the proposed studies will give insights into the molecular biology of CSCs and their role, if any, in racial differences between AA and CA TNBC patients and, also provide new targets for their elimination for effective therapy.