Steroid receptor coacfivator-3/amplified in breast cancer-1 (SRC-3/AIB1) is frequently overexpressed in breast carcinomas and can promote cell growth and resistance to endocrine therapies. In breast carcinomas overexpressing SRC-3, especially when in combination with activated HER2 signaling, the selective ER modulator (SERM) tamoxifen functions as an ER agonist. ER+/HER2+ tumors have a very poor response to tamoxifen treatment if SRC-3 is also overexpressed. Experimental targeting of SRC-3 can both a) augment the anti-estrogenic and anti-proliferative activity of tamoxifen in hormone-naive breast cancer cell lines, and b) restore the anti-estrogenic and anti-proliferative activity of tamoxifen in refractory breast cancer cell lines. Therefore, targeting SRC-3 expression and/or function is expected to enhance the activity of first-line conventional therapy and restore sensitivity in treatment-refractory breast cancer. Unfortunately, up to this point, SRC-3 has been considered """"""""undruggable"""""""" because it lacks a natural ligand-binding site that can be inhibited by small molecule compounds and protein:protein interacfions are difficult to disrupt. Importanfiy, the stability and activity of the SRC-3 protein are strongly regulated via its post-translational modificafion (PTM) by upstream kinase signaling networks, including protein kinase C (PKC). PKC family members can phosphorylate and protect SRC-3 from proteasome-mediated degradation. Given the critical role of SRC-3 in breast cancer and the lack of FDA-approved SRC-3 targeting agents, this proposal represents an innovafive hypothesis-driven approach, based on key basic research and robust preclinical evidence, to establish PKC SMls as first-in-class inhibitors of SRC-3 expression and function and as targeted therapies for use in combination with conventional agents for ER+ breast cancer. Preliminary studies demonstrate that PKC inhibitors (including agents that have been well-tolerated in clinical trials in other diseases) can, at clinically achievable and tolerated concentrafions, decrease SRC-3 protein expression, exert anticancer activity in SRC-3-overexpressing cell lines, enhance the anticancer activity of endocrine therapy in sensifive cells lines, and restore sensitivity to endocrine therapy in resistant breast cancer cell lines and xenografts.

Public Health Relevance

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
United States
Zip Code
Dasgupta, Subhamoy; Rajapakshe, Kimal; Zhu, Bokai et al. (2018) Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Nature 556:249-254
Rimawi, Mothaffar F; De Angelis, Carmine; Contreras, Alejandro et al. (2018) Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer. Breast Cancer Res Treat 167:731-740
Bajgain, Pradip; Tawinwung, Supannikar; D'Elia, Lindsey et al. (2018) CAR T cell therapy for breast cancer: harnessing the tumor milieu to drive T cell activation. J Immunother Cancer 6:34
Niravath, Polly; Chen, Bingshu; Chapman, Judy-Anne W et al. (2018) Vitamin D Levels, Vitamin D Receptor Polymorphisms, and Inflammatory Cytokines in Aromatase Inhibitor-Induced Arthralgias: An Analysis of CCTG MA.27. Clin Breast Cancer 18:78-87
Zhao, Na; Cao, Jin; Xu, Longyong et al. (2018) Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer. J Clin Invest 128:1283-1299
Bhat, Raksha R; Yadav, Puja; Sahay, Debashish et al. (2018) GPCRs profiling and identification of GPR110 as a potential new target in HER2+ breast cancer. Breast Cancer Res Treat 170:279-292
Guarducci, Cristina; Bonechi, Martina; Benelli, Matteo et al. (2018) Cyclin E1 and Rb modulation as common events at time of resistance to palbociclib in hormone receptor-positive breast cancer. NPJ Breast Cancer 4:38
Johnston, A N; Bu, W; Hein, S et al. (2018) Hyperprolactinemia-inducing antipsychotics increase breast cancer risk by activating JAK-STAT5 in precancerous lesions. Breast Cancer Res 20:42
Hertz, D L; Kidwell, K M; Hilsenbeck, S G et al. (2017) CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study. Breast Cancer Res Treat 166:277-287
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

Showing the most recent 10 out of 28 publications