Abstract 5422: Delphinidin dietary anthocyanidin modulates EGFR/HER-2 signaling pathway in breast cancer cells

Abstract

Abstract Breast cancer is the second leading cause of cancer deaths in women in the United States. The epidermal growth factor receptor (EGFR) and HER-2 are expressed in many breast cancer patients and are associated with poor prognosis. Over-expression of EGFR and HER-2 lead to resistance against tamoxifen, a selective estrogen receptor (ER) modulator. In addition, the efficacy of trastuzumab or lapatinib for the treatment of ER-negative breast cancer as a monotherapy or in combination with chemotherapy is limited in more advanced stages of HER-2 positive breast cancers by development of therapeutic resistance. Considerable attention has been devoted towards the development of dual inhibitors of EGFR and HER-2 for breast cancer treatment. Several of these inhibitors such as lapatinib have been tested preclinically and clinically, but their use is limited because of their unacceptable cytotoxic effects on normal cells or cancer cells acquire resistance to such treatment. Therefore, identification of a natural, nontoxic agent(s) capable of inhibiting both EGFR and HER-2 is of utmost importance. Delphinidin, an anthocyanidin, present in many pigmented fruits and vegetables possesses anti-oxidant and anti-proliferative properties. We showed that delphinidin inhibits constitutive and EGF-induced kinase activities of EGFR (Afaq et. al., Int. J Cancer 2008; 123: 1508-1515) in breast cancer cell lines. Recently, we found that delphinidin treatment also inhibits protein expression of HER-2 in breast cancer cells. The goal of the present study was to determine the antiproliferative and proapoptotic potentials of delphinidin in ER-positive and ER-negative breast cancer cell lines that overexpress EGFR/HER2. We first determined whether blockade of EGFR/HER-2 signaling pathways by delphinidin exhibits growth inhibitory effect. Delphinidin (5-60 μM; 72 hrs) treatment of ER-positive (BT-474 and MCF-7) and ER-negative (MDA-MB-231 and MDA-MB-468) breast cancer cells resulted in a dose-dependent decrease in cell viability but had only minimal effects on normal mammary epithelial cell line, 184A1. The signaling pathways induced by activated EGFR/HER-2 include the PI3K/AKT and MAPK, both of which play a role in the mitogenic and cell survival responses. Therefore, we analyzed the expression of these proteins and found that delphinidin treatment of ER-positive and ER-negative breast cancer cells inhibited the activation of PI3K and phosphorylation of AKT and MAPKs. Treatment of BT-474 and MDA-MB-231 cells with delphindin (5-60 μM; 72 hrs) resulted in (i) cleavage of PARP protein, (ii) activation of caspase-3 and-9, (iii) downregulation of cyclin D1 and Bcl-2, and (iv) increased expression of p27 and Bax. Based on these observations, we suggest that delphinidin, alone or as an adjuvant to current therapies, could be useful for the management of both ER-positive and ER-negative breast cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5422. doi:10.1158/1538-7445.AM2011-5422