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

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
1P50CA186784-01
Application #
8747142
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (M1))
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$260,403
Indirect Cost
$104,156
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030