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）：乳腺癌的发病率不断增加，无效妇女的全球疾病患病率使我们调查了荷尔蒙和生殖影响对乳腺癌风险的作用。为此，我们测试了年轻的处女和假性大鼠患7,12-二甲基苯子（A）蒽（DMBA）诱导的乳腺癌的敏感性。我们确认，卵巢功能的启动和第一次妊娠之间涵盖了最高敏感性的时期。第一次妊娠后给予的DMBA未能诱导乳腺癌，这是通过胎盘激素绒毛膜促性腺激素（HCG）对维生大鼠模仿的作用。另外，HCG还抑制了肿瘤进展。 HCG作用于卵巢，刺激雌激素，孕酮和抑制素的分泌。在这些激素刺激下，乳腺的末端芽分化为细胞增殖，类固醇激素受体含量和致癌物结合的iObules，并提高了致癌物加合的效率。分化还涉及分化标记物的表达，包括抑制素的合成，抑制素是一种具有肿瘤抑制活性的分泌蛋白，以及凋亡基因TRPM2，ICE，ICE，p53，C-MYC，WAF-1 /CIP-1，BCI-XS和p53的激活。在怀孕或HCG治疗期间和HCG治疗期间获得的乳腺RNA的聚类分析，并与含有5800只大鼠基因的cDNA阵列膜杂交，表明在不同的时间点表达了四种不同的基因聚类模式，从而使我们可以使我们与特定基因的不同阶段与特定基因的表达相关联。我们建议阐明HCG诱导正常乳腺的分化，防止癌症引发的机制是否与因抑制癌症进展而激活的机制不同，以及该作用是否特定于HCG，还是可以由卵巢类固醇激素或合成药物来重现。为了实现这些目标，我们建议：1）确定通过用HCG治疗对维生大鼠免受乳腺癌的保护是诱导乳腺上皮中基因组烙印的结果，该基因组烙印是针对这种激素的特异性或类似于类固醇激素治疗的结果； 2）确定HCG是否通过诱导通过细胞质甲基化介导的稳定的基因转录模式选择性抑制乳腺癌发生，还是其组蛋白乙酰化特性导致肿瘤抑制基因通过途径抑制肿瘤基因的重新激活，该途径是通过HCG或共同症状的型卵巢型和3的卵巢类固醇激素的hcg co;主要通过抑制甲基转移酶或通过组蛋白乙酰化来激活p53途径。通过这些研究获得的知识将巩固和扩大该模型的潜力，以根据基因表达调节的生理机制来制定预防和治疗乳腺癌的新型策略。