Androgens, Androgen Receptor Signaling and Breast Carcinogenesis

在项目1中，Brown博士、Tamimi博士和合作研究人员试图更好地了解雄激素受体(AR)在癌症风险和进展中的作用。虽然雄激素受体(AR)在正常乳腺上皮细胞和60%-70%的乳腺肿瘤中都有表达，但对雄激素在正常或恶性乳腺组织中的潜在作用知之甚少。以前研究AR信号与乳腺癌预后的研究仅限于样本大小，仅关注AR状态，很少考虑其他预后和治疗因素。为了探索这一具有临床挑战性的问题，这项基于人群的研究结合了护士健康研究(NHS)和乳房国际集团1-98(BIG 1-98)内分泌治疗试验的宝贵资源，以及AR信号和乳腺癌领域的流行病学、病理学和分子生物学方面的知名研究人员组成的合作团队。他们还将利用他们建立的识别类固醇受体的目标基因和协作转录因子的方法，除了在正常乳腺组织中进行单标记AR测试外，还将寻求建立AR图谱。这一特征将被用于使用良性乳腺疾病嵌套病例对照研究和正在进行的NHS队列研究中的组织来评估乳腺癌发展的风险。他们提出的对AR信号的全面评估和AR信号对乳腺癌风险影响的阐明将整合最先进的功能表观遗传学方法，如CHIP-SEQ，以剖析AR信号在乳腺癌风险中的作用，并允许对具有不同AR信号的女性的干预策略进行分层。此外，他们还将根据AR状态检查可能影响乳腺癌生存率的生活方式因素。这将提供对AR信号在乳腺癌发生和进展中的潜在机制的洞察，并可能确定乳腺癌幸存者中最有可能从改变行为(如增加体力活动水平)中受益的亚群。确定能提高乳腺癌女性患者生存率的生活方式因素具有重要的公共卫生意义，并可能为女性提供额外的动力来改变生活方式，这些改变可能会改变雄激素信号，从而改变她们患乳腺癌的风险。项目1研究人员的初步工作和其他已发表的研究表明，对于乳腺癌的结果，AR的作用取决于亚型。他们将在这些结果的基础上将AR转化为对亚型特定治疗的反应的预测性生物标记物和潜在的治疗靶点。开发针对不同乳腺癌亚型的AR靶基因集是这一建议中的一种新策略，可能解释与AR表达相关的乳腺癌不同预后。AR信号对这些乳腺癌亚型的治疗结果的研究具有重要的临床意义，并有可能通过确定AR调节将具有理想效果的临床情景，将他们的发现转化为临床实践。

In Project 1, Drs. Brown, Tamimi, and co-investigators seek to gain a better understanding of the role of the androgen receptor (AR) in cancer risk and progression. Although the androgen receptor (AR) is expressed in normal breast epithelial cells and in 60-70% of breast tumors, remarkably little is known about the potential role of androgens in normal or malignant breast tissue. Previous studies examining AR signaling and breast cancer prognosis have been limited in sample sizes, focused solely on AR status, and have taken into account very few other prognostic and treatment factors. To explore this clinically challenging issue, this population based study combines the valuable resources of the Nurses¿ Health Study (NHS) and the adjuvant Breast International Group 1-98 (BIG 1-98) endocrine therapy trial, with a collaborative team of established investigators in epidemiology, pathology and molecular biology in the field of AR signaling and breast cancer. They will also seek to establish an AR profile in addition to single marker AR testing in normal breast tissue utilizing methods they have established to identify the target genes and collaborating transcription factors for steroid receptors. This signature will be used to assess the risk of breast cancer development using tissue from the benign breast disease nested case-control study and the ongoing NHS cohort. Their proposed comprehensive assessment of AR signaling and the elucidation of the effects of AR signaling on breast cancer risk will integrate state-of-the-art functional epigenetics approaches such as ChIP-seq to dissect the role of AR signaling breast cancer risk, and would allow for the stratification of interventional strategies in women with different AR signaling. In addition, they will examine lifestyle factors that may modify breast cancer survival according to AR status. This will provide insight into underlying mechanisms of AR signaling on breast cancer development and progression, and may identify a subgroup of breast cancer survivors most likely to benefit from modifying their behaviors such as increasing physical activity levels. Identifying lifestyle factors that improve the survival among women with breast cancer has important public health implications and may provide women with additional motivation to make lifestyle changes that may alter the androgen signaling and hence their risk of breast cancer. Preliminary work from Project 1 investigators and other published studies demonstrate that for breast cancer outcomes, the role of AR is dependent on subtype. They will build on these results to translate AR into a predictive biomarker for response to subtype-specific therapies and a potential therapeutic target. The development of an AR target gene set specific to the different breast cancer subtypes is a novel strategy in this proposal and may explain the different prognosis associated with AR expression in breast cancer. The study of AR signaling on treatment outcomes in these breast cancer subtypes has important clinical implications and the potential for opportunities to translate their findings into clinical practice by identifying the clinical scenarios in which modulation of AR would have a desirable effect.