Abstract 1844: Apigenin prevents development of progestin-accelerated 7,12-dimethylbenz(a) anthracene (DMBA)-induced mammary tumors in Sprague-Dawley rats

Abstract

Abstract Post-menopausal women undergoing hormone replacement therapy (HRT) containing both progestins (P) and estrogens (E) are at an increased risk of developing breast cancer compared with those taking E alone. The biological mechanisms behind this phenomenon however, remain obscure. We showed that medroxyprogesterone acetate (MPA), a commonly used P, increases the production of the potent angiogenic growth factor VEGF in breast cancer cells that was blocked by the anti-progestin RU-486 suggesting the involvement of progesterone receptors (Int J Cancer, 2001, 92:469). This led to our hypothesis that P increases the angiogenic potential of latent tumorigenic cells in the breast, leading to development of palpable tumors. To prove this hypothesis, we developed in vivo models with human xenografts in mice (Cancer Res., 2007, 67:9929), and DMBA-induced tumors in rats (Clin Can Res, 2006, 12:4062). In both models, MPA accelerated tumor development that was blocked by RU-486. Since RU-486 has severe side-effects, we undertook studies aimed at identifying less toxic naturally-occurring compounds that might prevent P-dependent VEGF induction and tumor acceleration. We recently identified apigenin, a low molecular weight flavonoid commonly found in fruits and vegetables, which inhibited MPA-induced VEGF secretion from human breast cancer cells (Menopause, 2010, 17:1055). In this study we used the DMBA-induced mammary tumor model to determine whether apigenin prevents the development of P-accelerated tumors in vivo. Female Sprague-Dawley rats were treated with DMBA by oral gavage (Day 1). Seven days prior to implantation of 25 mg/60 day release MPA pellets (Day 28), ip administration of apigenin (50 mg/kg daily) began, and continued for 10 days. Animals were palpated for tumors every second day and experiment was terminated 60 days after DMBA treatment was initiated. Apigenin treatment led to a significant delay in the appearance of the first tumor, compared with MPA alone (56 vs 41 days; p<0.05, LIFETEST), as well as a reduction in tumor incidence and tumor multiplicity. Immunohistochemcial analysis with mammary tissue collected immediately after apigenin administration ceased revealed that even though apigenin decreased the overall incidence of MPA-accelerated tumors, it did not block or reverse DMBA-induced mammary tissue hyperplasia, suggesting that the effects of the flavonoid are exerted at a specific stage of tumor development. Further studies showed that apigenin suppressed both VEGF and its receptor, VEGFR-2, in the hyperplastic regions of the mammary gland. Thus apigenin appears to be a compound with useful anti-tumor and anti-angiogenic properties which could be given to post-menopausal women to prevent development of P-accelerated tumors. Support: COR award from the College of Vet Medicine and by research funds from RADIL, Univ. of Missouri. 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 1844. doi:10.1158/1538-7445.AM2011-1844