Genomic Markers of Breast Cancer Prevention Induced by hCG in Women at High Risk

描述(申请人提供)：这一假设得到了以下观察的支持：怀孕和母乳喂养降低了零星和BRCA1相关乳腺癌的风险，并且在实验模型中，用胎盘激素hCG治疗提供了类似程度的保护。由于BRCA1突变携带者的终生乳腺癌风险增加了85%，肿瘤发生的年龄明显低于散发性癌症，加上他们对内分泌和免疫治疗没有反应，因为他们对雌激素受体α(ERA)、孕激素受体(PR)和Her2这些恶化预后的因素呈阴性，这一高危人群是实施基于r-hCG作为化学预防药物的预防措施的理想目标。这一方法得到了我们的论证的支持，即怀孕诱导的乳房完全分化是为妇女和啮齿动物提供保护的主要机制之一，在这种机制中，用hCG治疗未成年大鼠可以防止化学诱导的乳腺癌的发生和发展。此外，我们已经证明，乳房的分化印记了一个特定的基因组特征，这是临产妇女的特征，因此可以作为指示终身乳腺癌风险降低的生物标记物。在这一探索性应用中，我们的目标是建立一个原则证据，即用重组人绒毛膜促性腺激素(r-hCG)治疗“高乳腺癌风险”女性将改变她们乳腺上皮的高风险基因组特征，使其与有早期完整第一个月妊娠史的女性相似。为此，将通过随机乳晕周围细针抽吸(RPFNA)从18名BRCA1有害突变的女性携带者中收集乳腺上皮细胞。将对细胞进行细胞病理学评估；提取RNA，通过基因芯片分析基因表达，并通过Ki67、ER和PR状态的免疫细胞化学确定细胞增殖，这些参数将作为“高危”基因组图谱的基线。我们建议测试90天(3个月)的重组人绒毛膜促性腺激素治疗是否会激活或下调与免疫监视、DNA修复、细胞程序性死亡、转录和染色质结构/激活物/共激活物相关的基因，与治疗前的基因组图谱相比，这些变化将表明“高风险”已被转换为“低风险”的基因组特征，例如在有早期第一次足月妊娠史的女性中发现的变化。这些知识将作为在该项目完成时建立新的基因组签名作为大型预防性临床试验的中间生物标记的基础。

DESCRIPTION (provided by applicant): This hypothesis is supported by the observations that pregnancy and breastfeeding reduce the risk of both sporadic and BRCA1-associated breast cancer, and that treatment with the placental hormone hCG confers a similar degree of protection in experimental models. Because the lifetime breast cancer risk of BRCA1 mutation carriers is increased by 85%, tumors arise in them at a significantly lower age than sporadic cancers, and in addition they are unresponsive to endocrine and immunotherapy due to their negativity for estrogen receptor alpha (ERa), progesterone receptor (PR), and Her2, factors that worsen their prognosis, this high risk population is an ideal target for implementing preventive measures based on the use of r-hCG as a chemopreventive agent. This approach is supported by our demonstration that the complete differentiation of the breast induced by pregnancy is one of the main mechanisms that confer protection to both women and rodents, in which treatment of virgin rats with hCG prevents the initiation and progression of chemically induced mammary cancer. Furthermore, we have demonstrated that the differentiation of the breast imprints a specific genomic signature that is characteristic of parous women and could serve therefore as a biomarker indicative of the lifetime decreased breast cancer risk. In this exploratory application we are aiming at establishing the proof of principle that treatment of "high breast cancer risk" women with recombinant human chorionic gonadotropin (r-hCG) will change their breast epithelium's high risk genomic profile to one similar to that identified in women with a history of early full first term pregnancy. For this purpose, breast epithelial cells will be collected by random periareolar fine needle aspiration (RPFNA) from 18 women carriers of BRCA1 deleterious mutations. Cells will be cytopathologically evaluated; RNA will be extracted for analysis of gene expression by cDNA microarray, and immunocytochemical determination of cell proliferation by Ki67, ER and PR status, parameters that will serve as a baseline of the "high risk" genomic profile. We propose to test whether a 90 day (3-month) treatment with r-hCG will activate or downregulate genes related to immune surveillance, DNA repair, programmed cell death, transcription, and chromatin structure/activators/co activators in comparison with the pre-treatment genomic profile, changes that will indicate that the "high risk" has been converted to a "low risk" risk genomic signature, such as that found in women with a history of early first full term pregnancy. This knowledge will serve as the basis for establishing novel genomic signatures as intermediate biomarkers for larger preventive clinical trials at the completion of this project.