Breast Cancer Therapy by Differentiation Gene Activation

通过分化基因激活治疗乳腺癌

• 批准号: 7071076
• 负责人: IRMA H. RUSSO
• 金额: $ 29.38万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7071076
• 关键词: acetylation; amidohydrolases; breast neoplasms; cancer prevention; carcinogenesis; cell differentiation; chorionic gonadotropin; cytosine; female; gene expression; genetic library; genetic transcription; genomic imprinting; hormone regulation /control mechanism; hormone therapy; in situ hybridization; laboratory rat; laser capture microdissection; mammary epithelium; methylation; methyltransferase; neoplasm /cancer chemotherapy; northern blottings; p53 gene /protein; polymerase chain reaction; sex hormones; tumor suppressor genes

DESCRIPTION (provided by applicant): The increasing incidence of breast cancer and the worldwide prevalence of the disease in nulliparous women led us to investigate the role played by hormonal and reproductive influences on breast cancer risk. For this purpose we tested the susceptibility of young virgin and of parous rats to develop 7,12-dimethylbenz(a)anthracene (DMBA) induced mammary cancer. We confirmed that the period of highest susceptibility is encompassed between the initiation of ovarian function and the first pregnancy. DMBA given after the first pregnancy failed to induce mammary cancer, an effect mimicked in virgin rats by a 21-day treatment with the placental hormone chorionic gonadotropin (hCG). In addition, hCG also inhibited tumor progression. HCG acts on the ovary, stimulating the secretion of estrogen, progesterone, and inhibin. Under these hormonal stimuli the mammary gland's terminal end buds differentiate into Iobules with reduced cell proliferation, steroid hormone receptor content, and carcinogen binding, and increased efficiency of carcinogen adduct removal. Differentiation also involved the expression of differentiation markers, including the synthesis of inhibin, a secreted protein with tumor suppressor activity, and activation of the apoptotic genes TRPM2, ICE, p53, c-myc, WAF-1 /CIP-1, bcI-XS, and p53. Cluster analysis of mammary gland RNAs obtained during and after pregnancy or hCG treatment and that were hybridized to cDNA array membranes containing 5,800 rat genes revealed that four different patterns of gene clustering were expressed at different time points, allowing us to correlate the different stages of development of the mammary gland with specific gene expression profiles. We propose to elucidate whether the mechanisms through which hCG induces differentiation of the normal breast, preventing the initiation of cancer, differ from those activated for the inhibition of cancer progression, and whether the effects are specific for hCG or could be reproduced by ovarian steroid hormones or synthetic drugs. For accomplishing these goals we propose to: 1) Determine whether the protection of virgin rats from mammary cancer by treatment with hCG is the result of the induction of a genomic imprinting in the mammary epithelium that is specific for this hormone, or similar to that induced by steroid hormone treatment; 2) Determine whether hCG selectively inhibits mammary carcinogenesis through the induction of a stable pattern of gene transcription mediated by cytosine methylation, or whether its histone acetylating properties lead to the reactivation of tumor suppressor genes through pathways exclusively activated by hCG or common for ovarian steroid hormones, and 3) Determine whether the inhibition of mammary carcinogenesis by hCG occurs predominantly by activation of the p53 pathway through inhibition of methyltransferase or through histone acetylation. Knowledge acquired through these studies will solidify and broaden the potential of this model for developing novel strategies for the prevention and treatment of breast cancer based on physiological mechanisms of gene expression regulation.

描述（由申请人提供）：乳腺癌发病率的增加以及该疾病在全球未产妇​​中的患病率促使我们研究激素和生殖影响对乳腺癌风险的影响。为此，我们测试了年轻处女和经产大鼠对 7,12-二甲基苯并（a）蒽 (DMBA) 诱发的乳腺癌的易感性。我们证实，最高易感期是在卵巢功能启动和第一次妊娠之间。第一次怀孕后给予 DMBA 未能诱发乳腺癌，通过胎盘激素绒毛膜促性腺激素 (hCG) 21 天治疗模拟了处女大鼠的效果。此外，hCG还抑制肿瘤进展。 HCG作用于卵巢，刺激雌激素、孕激素和抑制素的分泌。在这些激素刺激下，乳腺的终末芽分化为小球，细胞增殖、类固醇激素受体含量和致癌物结合减少，并且致癌物加合物去除效率增加。分化还涉及分化标志物的表达，包括抑制素（一种具有抑癌活性的分泌蛋白）的合成，以及凋亡基因 TRPM2、ICE、p53、c-myc、WAF-1 /CIP-1、bcI-XS 的激活和 p53。对怀孕期间或 hCG 治疗期间和之后获得的乳腺 RNA 进行聚类分析，并将其与包含 5,800 个大鼠基因的 cDNA 阵列膜杂交，结果表明在不同时间点表达了四种不同的基因聚类模式，使我们能够将不同的发育阶段关联起来具有特定基因表达谱的乳腺。我们建议阐明 hCG 诱导正常乳腺分化、防止癌症发生的机制是否不同于抑制癌症进展的机制，以及这种作用是否是 hCG 特有的，或者可以通过卵巢类固醇激素重现或合成药物。为了实现这些目标，我们建议：1) 确定用 hCG 治疗保护处女大鼠免受乳腺癌的影响是否是在乳腺上皮中诱导基因组印记的结果，该基因组印记对该激素具有特异性，或者与诱导的基因组印记相似。通过类固醇激素治疗； 2) 确定 hCG 是否通过诱导胞嘧啶甲基化介导的稳定基因转录模式选择性抑制乳腺癌发生，或者其组蛋白乙酰化特性是否通过 hCG 专门激活的途径或卵巢类固醇激素常见的途径导致抑癌基因重新激活，和 3) 确定 hCG 对乳腺癌发生的抑制作用是否主要是通过抑制甲基转移酶或通过组蛋白乙酰化激活 p53 途径而发生。通过这些研究获得的知识将巩固和扩大该模型的潜力，以开发基于基因表达调控的生理机制的预防和​​治疗乳腺癌的新策略。