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.
Project 1 focuses on an unanswered and key translational question in breast cancer risk and prevention. Its findings may have highly actionable therapeutic consequences as well. The focus of this project is entirely on AR in women at risk of developing breast cancer and in those with established disease. The truly unique aspect of this Project is the innovative approach to the evaluation of the presence of active androgen receptor signaling. The Project has direct clinical implications as well as translational impact. In addition to clarifying the prognostic role of AR signaling on risk and progression, it will begin to explain how and why AR signaling plays a role in breast cancer.
|Spangle, Jennifer M; Dreijerink, Koen M; Groner, Anna C et al. (2016) PI3K/AKT Signaling Regulates H3K4 Methylation in Breast Cancer. Cell Rep 15:2692-704|
|Montaser-Kouhsari, Laleh; Knoblauch, Nicholas W; Oh, Eun-Yeong et al. (2016) Image-guided Coring for Large-scale Studies in Molecular Pathology. Appl Immunohistochem Mol Morphol 24:431-5|
|Morganella, Sandro; Alexandrov, Ludmil B; Glodzik, Dominik et al. (2016) The topography of mutational processes in breast cancer genomes. Nat Commun 7:11383|
|Cheng, H; Liu, P; Ohlson, C et al. (2016) PIK3CA(H1047R)- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling. Oncogene 35:2961-70|
|Choi, Young Eun; Meghani, Khyati; Brault, Marie-Eve et al. (2016) Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian Cancer. Cell Rep 14:429-39|
|Ni, Jing; Ramkissoon, Shakti H; Xie, Shaozhen et al. (2016) Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med 22:723-6|
|Wang, Q; Liu, P; Spangle, J M et al. (2016) PI3K-p110Î± mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers. Oncogene 35:3607-12|
|Nik-Zainal, Serena; Davies, Helen; Staaf, Johan et al. (2016) Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534:47-54|
|Smid, Marcel; RodrÃguez-GonzÃ¡lez, F GermÃ¡n; Sieuwerts, Anieta M et al. (2016) Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration. Nat Commun 7:12910|
|Johnson, Shawn F; Cruz, Cristina; Greifenberg, Ann Katrin et al. (2016) CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer. Cell Rep 17:2367-2381|
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