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。TNBCs临床缺乏雌激素受体(ER)-α的表达， 孕激素受体和HER-2，不能用目前的内分泌或HER2靶向治疗。 TNBCs是异质性的，经常发生在非裔美国人和年轻女性中。尽管最初 对某些化疗药物有反应的TNBCs倾向于早期复发和转移，导致临床不良。 结果。我们的首要任务是确定新的治疗靶点，这些靶点可以转化为临床。我们 预测被称为ER-β的第二个ER基因产物的表达可能在所有或亚组中都是这样的靶点 在TNBCs中。在对非裔美国人和高加索女性的TNBC活检样本的初步工作中，我们 发现ER-β1的表达与接受联合治疗的患者5年总生存率显著下降相关 化疗和较短的无病间隔时间。此外，一组TNBC细胞系都表现出显著的 ER-β的表达，在非裔美国人的细胞中检测到相对较高的水平。其他报告也包括 在乳腺癌中发现ER-β与更具侵袭性的表型有关，特别是在非裔美国人中。 因此，我们假设ER-β存在于大多数TNBCs中，并调节肿瘤的进展。此外, 初步数据显示，胰岛素样生长因子-2(IGF-2)，已知与肿瘤促进有关，是 在TNBC标本中也有表达，并刺激ER-βmRNA的高表达以促进TNBC 进步。这一途径的促生长作用可能部分归因于下游促进作用 血管内皮生长因子、两用调节素和WNT-10b活性。该项目的目标是：1)使用组织微阵列(TMA) 评估ER-β形式和IGF-2的表达及其在慢性粒细胞白血病患者中的临床后果 不同种族/民族与TNBC；2)评估ER-β对细胞增殖、凋亡和信号转导的影响 体外培养的TNBC细胞与生长因子IGF-2和PD-L1的相互作用；3)测定有效内质网的活性。 β激动剂和拮抗剂对人TNBC植入免疫缺陷小鼠体内进展的影响。这 工作可能有助于解决种族/民族少数群体和未得到充分服务的群体之间癌症负担不平等的问题 代表了TNBC-TMA，并评估这些因素与癌症生物学的相互作用-即 重要激素/生长因子信号通路在TNBC患者中的表达和活性

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.