Biologic Factors in Triple-Negative Breast Cancer Health Disparities

项目摘要 三阴性乳腺癌（TNBC）发生在10-15%的患者中，但这种疾病亚型占 几乎占所有乳腺癌死亡人数的一半。TNBC缺乏雌激素受体（ER）-α的临床表达， 孕激素受体和HER-2，不能用目前的内分泌或HER 2靶向疗法治疗。 TNBC是异质性的，经常发生在非洲裔美国人和年轻女性中。虽然最初 对某些化疗有反应的TNBC倾向于早期复发和转移，导致不良的临床疗效。 结果。我们的首要任务是确定可用于临床的新治疗靶点。我们 预测称为ER-β的第二ER基因产物的表达可能是所有或子集中的这样的靶点 的TNBC。在对来自非洲裔美国人和高加索妇女的TNBC活检标本的初步工作中，我们 发现ER-β 1表达与接受以下治疗的患者的5年总生存率显著降低相关： 化疗和更短的无病间隔。此外，一组TNBC细胞系均表现出显著的细胞毒性。 ER-β表达，在非洲裔美国人的细胞中检测到相对较高的水平。其他报告还 发现ER-β与乳腺癌中更具侵袭性的表型相关，特别是在非洲裔美国人中。 因此，我们假设ER-β存在于大多数TNBC中并调节肿瘤进展。此外，本发明还提供了一种方法， 初步数据显示，已知与肿瘤促进相关的胰岛素样生长因子-2（IGF-2）， 也在TNBC标本中表达，并刺激ER-β mRNA的高表达以促进TNBC 进展这一途径的生长刺激作用可能部分是由于下游的行动，以促进 VEGF、双调蛋白和Wnt-10 b活性。本项目的目标是：1）使用组织微阵列（TMA） 评估ER-β形式和IGF-2的表达，以及表达的临床后果， 2）评估ER-β对细胞增殖、凋亡和信号传导的影响 体外与TNBC细胞中生长因子（IGF-2）和PD-L1的相互作用; 3）测定可用的ER-1的活性。 在免疫缺陷小鼠体内，β激动剂和拮抗剂对人TNBC植入物进展的影响。这 工作可能有助于解决少数种族/族裔和服务不足群体之间的癌症负担不平等问题 在TNBC-TMA中代表，并评估这些因素与癌症生物学的相互作用，即 在患有TNBC的患者中重要激素/生长因子信号传导途径的表达和活性。

Project Summary Triple-negative breast cancers (TNBC) occur in 10-15% of patients, yet this disease subtype accounts for almost half of all breast cancer deaths. TNBCs lack clinical expression of estrogen receptor (ER)-alpha, progesterone receptor and HER-2 and cannot be treated with current endocrine or HER2-targeted therapies. TNBCs are heterogeneous and occur often in African American and younger women. Although initially responsive to some chemotherapies, TNBCs tend to relapse and metastasize early, leading to poor clinical outcome. Our highest priority is to define new therapeutic targets that can be translated to the clinic. We predict that expression of a second ER gene product, termed ER-beta, may be such a target in all or subsets of TNBCs. In preliminary work with TNBC biopsy specimens from African American and Caucasian women, we find ER-beta1 expression correlates with significantly worse 5-year overall survival in patients treated with chemotherapy and with shorter disease-free intervals. Further, a panel of TNBC cell lines all exhibit significant ER-beta expression, with relatively higher levels detected in cells from African Americans. Other reports also find ER-beta associates with more aggressive phenotypes in breast cancer, particularly in African Americans. Thus, we hypothesize that ER-beta occurs in most TNBCs and modulates tumor progression. In addition, preliminary data show that insulin-like growth factor-2 (IGF-2), known to associate with tumor promotion, is also expressed in TNBC specimens and stimulates high expression of ER-beta mRNA to promote TNBC progression. Growth-stimulating effects of this pathway may be due in part to downstream actions to promote VEGF, amphiregulin and Wnt-10b activity. Aims of this project are to: 1) use tissue microarrays (TMA) to assess expression of ER-beta forms and IGF-2 as well as clinical consequences of expression in individuals of diverse race/ethnicity with TNBC; 2) assess effects of ER-beta on cell proliferation, apoptosis and signaling interactions with growth factors (IGF-2) and PD-L1 in TNBC cells in vitro; 3) determine activity of available ER- beta agonists and antagonists on progression of human TNBC implants in immunodeficient mice in vivo. This work may help address the unequal burdens of cancer among racial/ethnic minorities and underserved groups represented in the TNBC-TMA and assess the interplay of these factors with cancer biology—namely expression and activity of important hormone/growth factor signaling pathways in patients afflicted with TNBC.