Abstract 2825: Prevention of breast tumor growth by an extract from the muscadine grape

Grape extracts have garnered attention as chemopreventive agents due their anti-proliferative, anti-inflammatory and anti-oxidant properties. The muscadine grape (Vitis rotundifolia) has a distinct phytochemical composition compared to other grape varieties. The current study examines the preventive effects of a proprietary muscadine grape extract (MGE) on breast cancer formation. The proliferation of actively growing human ER+ or triple negative breast cancer cells was significantly reduced by MGE from grape seeds or skins with an associated decrease in phospho-ERK, suggesting that MGE inhibits breast cancer cell proliferation through a reduction in activation of growth-promoting kinases. Female FVB-Tg(MMTV)NKAMul/J transgenic mice with an activated rat Erbb2 oncogene expressed specifically in the mammary gland (c-neu mice) form mammary tumors by 6-8 months of age. c-Neu mice were treated with MGE in the drinking water (approximately 1.0 mg phenolics/25 g mouse) beginning at weaning and were sacrificed at 7½ months of age. No changes were observed in eating or drinking habits or in gross body, heart or kidney weight, suggesting that the MGE was well tolerated. Although all of the mice developed breast tumors, MGE significantly reduce tumor burden compared to the tumor tissue in mice drinking regular water (9.2±1.2 g versus 3.6±1.4 g, p = 0.001, n = 8-10). A group of c-Neu mice were also sacrificed at 4 months of age, once tumors were palpable, to assess tumor multiplicity. Both tumor burden (1.4±.3 g versus 0.3±0.1 g, p = 0.007) and tumor multiplicity (11.8±2.1 versus 5.1±0.9, p = 0.013, n = 6-11) were reduced in mice treated with MGE. Tumor tissue sections from mice administered MGE had a significant decrease in the proliferation marker Ki67 compared to tumors from control animals [310±92 versus 166±70 immunoreactive cells/field, p = 0.002], in agreement with the reduction in proliferation observed in vitro. Tumor sections from c-neu mice were incubated with an antibody to the endothelial cell marker, CD34, and vessels were identified by a combination of morphology and positive CD34 immunoreactivity; MGE significantly reduced blood vessel density in breast tumor tissue compared to tumors from mice drinking regular water [5.7±0.6 versus 3.6±0.9, p = 0.022], suggesting that the grape extract attenuates tumor angiogenesis. Interstitial tumoral fibrosis was quantified in breast tumor tissue sections using picrosirius red, a nonspecific collagen stain. MGE treatment markedly decreased interstitial fibrosis as compared to the tumors from control animals [2.79±0.70% versus 0.14±0.04%, p = 0.0005], indicating that the extract reduces cancer-associated fibrosis in breast tumors. Taken together, these studies suggest that MGE reduces both breast tumor burden and multiplicity, through decreasing proliferation, angiogenesis and fibrosis, suggesting that extracts from muscadine grapes may represent a novel nutraceutical for the prevention of breast cancer. Citation Format: Patricia E. Gallagher, E. Ann Tallant. Prevention of breast tumor growth by an extract from the muscadine grape. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2825. doi:10.1158/1538-7445.AM2015-2825