Androgens, Androgen Receptor Signaling and Breast Carcinogenesis

在项目1中，Brown博士，Tamimi博士和合作研究者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信号和乳腺癌预后的研究在样本量方面受到限制，仅关注AR状态，并且考虑了很少的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）和辅助乳腺国际组1-98（BIG 1-98）内分泌治疗试验的宝贵资源，以及AR信号传导和乳腺癌领域流行病学，病理学和分子生物学研究人员的合作团队。除了在正常乳腺组织中进行单一标记物AR测试外，他们还将寻求建立AR谱，利用他们已经建立的方法来识别靶基因和类固醇受体的协作转录因子。该签名将用于使用来自良性乳腺疾病巢式病例对照研究和正在进行的NHS队列的组织评估乳腺癌发展的风险。他们提出的AR信号传导的综合评估和AR信号传导对乳腺癌风险的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信号传导乳腺癌风险的作用，并允许对具有不同AR信号传导的女性进行干预策略分层。此外，他们将根据AR状态检查可能改变乳腺癌生存率的生活方式因素。这将为深入了解AR信号传导对乳腺癌发展和进展的潜在机制提供帮助，并可能确定一个最有可能从改变其行为（如增加体力活动水平）中受益的乳腺癌幸存者亚组。确定提高乳腺癌妇女生存率的生活方式因素具有重要的公共卫生意义，并可能为妇女提供额外的动力，改变生活方式，改变雄激素信号传导，从而改变她们患乳腺癌的风险。来自项目1研究人员和其他已发表研究的初步工作表明，对于乳腺癌结局，AR的作用取决于亚型。他们将在这些结果的基础上将AR转化为对亚型特异性治疗反应的预测生物标志物和潜在的治疗靶点。开发一个特定于不同乳腺癌亚型的AR靶基因集是该提案中的一种新策略，可以解释与乳腺癌中AR表达相关的不同预后。AR信号对这些乳腺癌亚型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调节将产生理想效果的临床情况，将其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.