Abstract P4-09-05: Preventive efficacy of the Chinese nutritional herb epimedium grandiflorum in a preclinical cell culture model for luminal A molecular subtype of breast cancer

Abstract

Abstract Background: The Luminal A molecular sub-type of clinical breast cancer expresses estrogen receptor (ER) and progesterone receptor (PR), but lacks the expression of HER-2 oncogene. This cancer sub-type responds to endocrine therapy involving the use of selective estrogen receptor modulators or inhibitors of estrogen biosynthesis. Conventional therapeutic options are frequently associated with acquired tumor resistance and systemic toxicity, and therefore, emphasize a need for identification of promising new non-toxic agents for secondary prevention. Nutritional substances that do not incur long-term toxicity represent ideal candidates. Nutritional herbs have been used in traditional Chinese medicine for a variety of health related issues, including prevention of breast cancer. Methods: The present study utilized the human mammary carcinoma derived ER+/PR+/HER-2- MCF-7 cells as a model for the Luminal A breast cancer to examine the preventive efficacy of non-fractionated aqueous extract from Epimedium grandiflorum (EG), a popular Chinese nutritional herb. Anchorage dependent growth, cell cycle progression, cellular metabolism of 17b-estradiol (E2), and anchorage independent colony formation represented the quantitative end point biomarkers for preventive efficacy. Results: Maintenance of MCF-7 cells in a chemically defined serum depleted culture medium (serum 0.7%, E2<1 nM) retained their cellular growth promoting response to the physiologically relevant concentration range of 1 nM to 20 nM E2, exhibiting a 10.3% to a 91.9% increase in the viable cell number, respectively. A 7 day treatment of MCF-7 cells with EG resulted in a dose dependent inhibition of E2 promoted growth (EG IC50: 0.49%). At its maximum cytostatic concentration, EG inhibited cell cycle progression via G1 arrest, resulting in a 1.6 fold increase in the G1:S+G2/M ratio, and modulated the cellular metabolism of E2 in favor of formation of anti-proliferative metabolites 2-hydroxyestrone (2-OHE1) and estriol (E3), exhibiting a 5.1 and a 7.6 fold increase, respectively. In addition, EG produced a favorable 3.9 fold increase in the 2-OHE1: 16α-OHE1 ratio, an endocrine biomarker of breast cancer risk. A 21 day treatment of MCF-7 cells with EG produced a dose dependent inhibition in anchorage independent growth (EG IC50: 0.49%; IC90: 1.03%). Conclusions: These data demonstrate the growth inhibitory effects of EG and identify clinically relevant mechanistic leads for its preventive efficacy. The present approach promises to facilitate identification of new efficacious herbs for the secondary prevention of the Luminal A subtype of clinical breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-09-05.