The androgen receptor (AR) is known to be expressed in the majority of estrogen receptor (ER) alphapositive human breast tumors. By gene expression profiling, we discovered elevated AR RNA in clinical breast tumors resistant to antiestrogen therapy with tamoxifen (Tarn). We have shown that overexpression of AR causes ER alpha-positive MCF-7 breast cancer cells to become resistant to the growth-inhibitory effects of Tam and to estrogen withdrawal, which models the therapeutic action of aromatase inhibitors [Als]). This endocrine resistance could be reversed by the AR antagonist bicalutamide, or by AR knockdown. Furthermore, in AR-overexpressing breast cancer cells, Tam induced rather than repressed ERalpha's transcriptional activity, and this could also be reversed by bicalutamide. We therefore hypothesize that AR overexpression is a novel mechanism of resistance to ER-targeted therapies. We have developed this translational study to extend these findings, to determine how AR causes resistance to Tam and Als and thus identify potential predictive markers for resistance and possible intermediate targets for reversing resistance, and finally to test this hypothesis in an initial clinical trial using bicalutamide to restore response in breast cancer patients whose tumors become resistant to Tam or Al treatment. Our proposed Aims are: (1) To determine the contribution of AR crosstalk with growth factor receptors and ER alpha in the resistant phenotype associated with AR overexpression using various signal transduction inhibitors and cell biological assays. (2) To determine how AR overexpression causes Tarnmediated nuclear ER transcriptional activation, exploring genomic AR actions. (3) To examine how AR overexpression affects survival pathways during estrogen deprivation with an Al. (4) To determine whether the AR antagonist bicalutamide can reverse endocrine resistance in breast cancer patients progressing on Tam or an Al in a Phasei/ll clinical trial. These studies will employ techniques to explore the molecular mechanisms of AR action in breast cancer cells, which is an understudied area. We will identify whether specific components of the AR signaling pathway can be exploited to reverse endocrine resistance. We anticipate that AR will become an important new marker of endocrine resistance, and with the availability of an FDA-approved agent to block its effects (bicalutamide), we can rapidly translate our results into a possible new strategy for maintaining the benefits of endocrine therapy in breast cancer patients.

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Baylor College of Medicine
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Yu, L; Liang, Y; Cao, X et al. (2017) Identification of MYST3 as a novel epigenetic activator of ER? frequently amplified in breast cancer. Oncogene 36:2910-2918
Holloway, Kimberly R; Sinha, Vidya C; Bu, Wen et al. (2016) Targeting Oncogenes into a Defined Subset of Mammary Cells Demonstrates That the Initiating Oncogenic Mutation Defines the Resulting Tumor Phenotype. Int J Biol Sci 12:381-8
Malorni, Luca; Giuliano, Mario; Migliaccio, Ilenia et al. (2016) Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance. Mol Cancer Res 14:470-81
Fu, Xiaoyong; Jeselsohn, Rinath; Pereira, Resel et al. (2016) FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer. Proc Natl Acad Sci U S A 113:E6600-E6609
Erdem, Cemal; Nagle, Alison M; Casa, Angelo J et al. (2016) Proteomic Screening and Lasso Regression Reveal Differential Signaling in Insulin and Insulin-like Growth Factor I (IGF1) Pathways. Mol Cell Proteomics 15:3045-57
Chaluvally-Raghavan, Pradeep; Jeong, Kang Jin; Pradeep, Sunila et al. (2016) Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer. Cell Rep 15:1493-1504
Dobrolecki, Lacey E; Airhart, Susie D; Alferez, Denis G et al. (2016) Patient-derived xenograft (PDX) models in basic and translational breast cancer research. Cancer Metastasis Rev 35:547-573
Shi, Aiping; Dong, Jie; Hilsenbeck, Susan et al. (2015) The Status of STAT3 and STAT5 in Human Breast Atypical Ductal Hyperplasia. PLoS One 10:e0132214
Canfield, Kaleigh; Li, Jiaqi; Wilkins, Owen M et al. (2015) Receptor tyrosine kinase ERBB4 mediates acquired resistance to ERBB2 inhibitors in breast cancer cells. Cell Cycle 14:648-55
Sine, Jessica; Urban, Cordula; Thayer, Derek et al. (2015) Photo activation of HPPH encapsulated in ""Pocket"" liposomes triggers multiple drug release and tumor cell killing in mouse breast cancer xenografts. Int J Nanomedicine 10:125-45

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