REGULATION OF BRCA1 SIGNALING AND FUNCTION BY HEREGULIN

HEREGULIN 对 BRCA1 信号传导和功能的调节

• 批准号: 6167181
• 负责人: HAVA Karsenty AVRAHAM
• 金额: $ 13.05万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6167181
• 关键词: biological signal transduction; brca gene; breast neoplasms; epidermal growth factor; gene expression; growth factor receptors; heregulin; phosphoproteins; phosphorylation; protein structure function; tissue /cell culture; transcription factor

Breast cancer is a complex, multifactorial disease with both genetic and environmental components. Germline mutations in the breast cancer susceptibility gene BRCA1 account for the increased risk of early onset of familial breast cancer, whereas overexpression of the ErbB family of receptor tyrosine kinases has been linked to the development of non-familial or sporadic breast cancer. The breast cancer susceptibility gene (BRCA1) encodes a nuclear phosphoprotein that acts as a tumor suppressor, while activation of the ErbB receptors by heregulin (HRG) promotes cell growth in breast epithelial cells. The possibility that ErbB-2 receptor activation by heregulin can modulate BRCA1 function presents a new approach and a novel mechanism in understanding breast cancer biology. To assess if there may be a link between these two regulatory molecules, we aim to investigate the effect of activation of the ErbB receptor pathway by HRG on BRCA1 function. Our recent studies showed that HRG stimulation induced the phosphorylation of BRCA1, which was mediated by the phosphatidylinositol-3 kinase (PI-3K)/AKT pathway. In addition, HRG as well as constitutively active p110 and AKT blocked the BRCA1-induced activation of the cyclin dependent kinase inhibitor p21WAF1/CIP1 promoter and the growth suppressive function of BRCA1. These results suggest that inhibition of BRCA1 function by HRG could contribute to the dysregulated cell growth associated with sporadic breast cancer. These data lead us to hypothesize that: (1) BRCA1 might play a role not only in the onset of familial breast cancer but also in sporadic breast cancer; (2) Inhibition of normal BRCA1 function by HRG could contribute to the dysregulated cell growth associated with sporadic breast cancer; and (3) BRCA1 expression and phosphorylation might be regulated by the Forkhead transcription factor (FKHRL1) and the phosphatase and tensin homolog located on chromosome (PTEN) via the PI-3K/AKT pathway. Therefore, the goal of this study is to examine the regulation of BRCA1 function and signaling in breast cancer cells upon HRG stimulation. The experiments presented here are designed to elucidate the mechanisms by which HRG modulates the function of BRCA1 and its regulation by PTEN and FKHRL1. These studies should provide a novel approach with new insights into the biology of BRCA1 and HRG function in breast cancer, and will assist in efforts to understand the regulation and function of BRCA1 mediated by growth factors in breast cancer development. In addition, these studies will provide a scientific basis for the manipulation of BRCA 1 for the treatment of this disease.

乳腺癌是一种复杂的多因素疾病，具有遗传和环境成分。 乳腺癌敏感性基因BRCA1中的种系突变造成了家族性乳腺癌早期发作的风险增加，而ERBB受体酪氨酸激酶家族的过表达与非家庭或零星乳腺癌的发展有关。 乳腺癌的易感基因（BRCA1）编码可作为肿瘤抑制剂的核磷酸蛋白，而Lhongulin（HRG）激活ERBB受体可促进乳腺上皮细胞中的细胞生长。 ERBB-2受体激活的可能性可以调节BRCA1功能提出了一种新的方法和一种理解乳腺癌生物学的新机制。 为了评估这两个调节分子之间是否存在联系，我们旨在研究HRG通过HRG对BRCA1功能激活ERBB受体途径的影响。我们最近的研究表明，HRG刺激诱导BRCA1的磷酸化，该磷酸化是由磷脂酰肌醇-3激酶（PI-3K）/AKT途径介导的。 此外，HRG以及组成型活性P110和AKT阻止了BRCA1诱导的细胞周期蛋白依赖性激酶抑制剂P21WAF1/CIP1启动子的激活以及BRCA1的生长抑制功能。 这些结果表明，HRG对BRCA1功能的抑制可能导致与零星乳腺癌相关的细胞生长失调。这些数据导致我们假设：（1）BRCA1不仅在家族性乳腺癌的发作，而且在零星的乳腺癌中发挥作用； （2）HRG抑制正常的BRCA1功能可能导致与零星乳腺癌相关的细胞生长失调； （3）BRCA1表达和磷酸化可能由叉状转录因子（FKHRL1）以及位于染色体（PTEN）上的磷酸酶和Tensin同源物调节。因此，这项研究的目的是检查HRG刺激后乳腺癌细胞中BRCA1功能和信号传导的调节。 此处介绍的实验旨在阐明HRG调节BRCA1及其通过PTEN和FKHRL1调节的机制。 这些研究应提供一种新的方法，并对乳腺癌中BRCA1和HRG功能的生物学有了新的见解，并将努力理解由生长因子在乳腺癌发展中介导的BRCA1的调节和功能。此外，这些研究将为操纵BRCA 1治疗该疾病提供科学基础。