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

描述（由申请人提供）：非裔美国人（AA）和白种人（CA）女性患乳腺癌的结果存在种族差异。例如，AA女性的乳腺癌死亡率可能是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为三阴性乳腺癌（TNBC），更常被诊断为晚期，可能发生转移，并且通常对治疗无反应（1,2）。虽然部分患者对化疗有反应，但最初化疗后1 - 3年内肿瘤复发，5年内死亡率高(3)。我们的研究小组和其他人报道了癌症干细胞样细胞（CSCs或肿瘤起始细胞），其特征是自我更新和抵抗治疗导致肿瘤复发和转移，与其他类型的乳腺癌相比，TNBC女性中特别丰富（4,5）。我们还观察到，与来自CA TNBC患者的MDA-MB-231和BT549细胞系的CSCs相比，来自AA TNBC患者的CRL-2335和MDA-MB468细胞系中分离的CSCs (i)在顺platin加肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）治疗后（ii）显示出更长的生存期和形成乳腺球的能力，miR-100和miR-23b的表达降低，FZD8的表达显著增加。Wnt受体之一（也是miR-100的靶标）在CSC更新中起主要作用，与来自CA TNBC患者的MDA-MB-231和BT549细胞系相比。因此，我们假设癌症干细胞（CSCs）自我更新的差异导致了TNBC中的种族差异。为了验证我们的假设，我们有两个具体目标：目标1：确定非裔美国女性与白人女性TNBC中CSCs的作用。目的2：建立一种新的肿瘤模型，以解决microrna （miR-100和miR-23b）在体内CSCs自我更新、肿瘤进展和治疗中的作用。上述研究的成功完成将有助于深入了解CSCs的分子生物学及其在AA和CA TNBC患者种族差异中的作用（如果有的话），并为消除其有效治疗提供新的靶点。

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.