Abstract P3-09-04: Growth inhibitory effects of Cornus officinalis on a model for triple negative breast cancer

Abstract

Abstract Background: The triple negative breast cancer (TNBC) molecular subtype is characterized by the absence of estrogen receptor-α (ER-α), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) expressions. TNBC is refractory to endocrine and to HER-2 selective therapy, while options for the treatment of choice involving high dose Anthracyclin/Taxol based conventional chemotherapy and/or small molecule inhibitor based targeted therapy are associated with systemic toxicity and acquired tumor resistance, leading to compromised efficacy. These limitations emphasize a need to identify efficacious non-toxic agents for secondary prevention/therapy of TNBC. Cornus officinalis (CO) is a Chinese herb of a nutritional nature in the form of a fruit. It is a major ingredient herb in some well-known Chinese herbal formulations for health management purposes. Growth inhibitory efficacy of CO in a model for ER positive Luminal A molecular subtype of clinical breast cancer is associated with abrogation of estradiol promoted growth via generation of anti-proliferative estradiol metabolites [Telang et al: Mol. Med. Rep. 5: 20-28, 2012].The present study examines the growth inhibitory effects of CO, and identifies possible molecular targets for its efficacy in a pre-clinical cell culture model for TNBC. Experimental model, Herbal Extract and Biomarkers: The human mammary carcinoma-derived ER-α negative, PR negative and HER-2 negative MDA-MB-231 cell line represents the model for TNBC. Non-fractionated aqueous extract from CO represents the test agent. Anchorage dependent growth, anchorage independent (AI) colony formation, cell cycle progression, cellular apoptosis and relevant pathway specific mechanistic assays represent the biomarkers for efficacy. Results: Treatment of MDA-MB-231 cells with CO extract induces substantial dose dependent cytostatic growth arrest (IC50:0.1%; IC90:0.5%), and strongly inhibits AI colony formation. Within the cytostatic range CO inhibits G1 to S phase transition leading to G1 arrest that is accompanied by decreased expressions of Cyclin D1 and p-RB. Cellular apoptosis induced by CO is associated with modulation of the BAX-BCL-2 pathway, and up-regulation of the pro-apoptotic Caspase 3/7 activity. Conclusions: These data provide a mechanistic evidence for efficacy of CO as a naturally occurring nutritional substance in a cell culture model for TNBC. The present study validates a mechanism based approach to prioritize efficacious non-toxic herbal extracts for secondary prevention/therapy of the TNBC molecular subtype of clinical breast cancer. Citation Format: Telang NT, Nair HB, Wong GYC. Growth inhibitory effects of Cornus officinalis on a model for triple negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-09-04.