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

描述(由申请人提供)：在非裔美国人(AA)和高加索人(CA)女性之间，乳腺癌的结果存在种族差异。例如，AA妇女的乳腺癌死亡率可能比CA妇女高三倍，尽管AA妇女的发病率较低(1)。与CA妇女相比，AA妇女患三阴性乳腺癌(TNBC)的年龄更早，更容易被诊断为晚期，更有可能经历转移，而且往往对治疗没有反应(1，2)。虽然一些患者对化疗有反应，但最初，肿瘤在化疗后1至3年内复发，5年内死亡率高(3)。我们的研究小组和其他人已经报道，与其他类型的乳腺癌相比，肿瘤干细胞(CSCs或肿瘤启动细胞)在患有TNBC的女性中尤其丰富，这种细胞具有自我更新和对导致肿瘤复发和转移的治疗耐受的特点。我们还观察到，在AA TNBC患者来源的CRL-2335和MDA-MB468细胞系中分离的CSCs比来自CA TNBC患者来源的MDA-MB-231和BT549细胞系的CSCs具有更长的存活时间和形成乳房的能力(II)经顺铂加肿瘤坏死因子相关的凋亡诱导配体(TRAIL)处理后，miR-100和miR-23b的表达降低，而在CSC更新中起主要作用的Wnt受体之一(也是miR-100的靶点)FZD8的表达显著增加。与来自CA TNBC患者的MDA-MB-231和BT549细胞系相比。因此，我们假设肿瘤干细胞(CSCs)自我更新的差异导致了TNBC的种族差异。为了验证我们的假设，我们有两个具体的目标：目标1：确定CSCs在非裔美国女性与高加索女性的TNBC中的作用。目的：建立一种新的肿瘤模型，研究microRNAs(miR-100和miR-23b)在肿瘤干细胞自我更新、肿瘤进展和体内治疗中的作用。这项拟议研究的成功完成将使人们深入了解CSCs的分子生物学及其在AA和CA TNBC患者之间的种族差异中的作用，并为消除它们以进行有效的治疗提供新的靶点。

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.