Novel strategies for prevention of breast cancer are desirable mainly because many risk factors associated with this disease are not easily modifiable. In addition, currently available clinical options for prevention of breast cancer (eg, selective estrogen receptor modulators and aromatase inhibitors) are sub-optimal. Recent literature highlights merit of plants used in Ayurvedic medicine, which has been practiced for centuries in India for treatment of different disorders, for identification of novel cancer preventive agents. Withania somnifera (also known as Ashwagandha) is one such medicinal plant that is used to alleviate a variety of symptoms. In experimental models, the known pharmacological effects of Withania somnifera include cardioprotection from ischemia reperfusion injury, inhibition of experimental Parkinsonism, suppression of hepatic lipid peroxidation, antibacterial effects, and anticancer effects. Anticarcinogenic effect of Withania somnifera is ascribed to withanolides such as withaferin A (WA). We have shown previously that WA treatment inhibits growth of cultured and xenografted human breast cancer cells by causing apoptotic cell death. The present study extends these observations and determines efficacy of WA for prevention of breast cancer in a clinically-relevant transgenic mouse model (MMTV-neu). Incidence and burden of mammary cancer and pulmonary metastasis were scored in female MMTV-neu mice after 28 weeks of intraperitoneal administration (three times/week) with 0.1 mg WA (n = 32) or vehicle (n = 29). This mild-regimen of WA administration resulted in a statistically significant decrease in macroscopic (palpable) tumor size, microscopic tumor area, and incidence of pulmonary metastasis. For example, the mean wet weight of the palpable tumor was lower by 50% in WA-treated mice compared with control mice (P = 0.03). Likewise, the area of invasive mammary cancer was lower by 95.14% in WA-treated mice compared with control mice (P = 0.05). The WA-treated mice exhibited a 72.8% decrease in incidence of pulmonary metastasis compared with the control mice (P = 0.02). Immunohistochemistry revealed reduced expression of HER-2 in tumors from WA-treated mice compared with control. Furthermore, consistent with cellular observations, mammary cancer prevention by WA treatment was associated with increased apoptosis index, inhibition of complex III activity, and increased staining for 8-oxo-dG (an indicator of oxidative stress). In conclusion, the results of the present study indicate that WA inhibits mammary carcinogenesis in a transgenic mouse model by causing apoptosis. This study was supported by the grant CA142604 awarded by the National Cancer Institute.

Citation Format: Eun-Ryeong Hahm, Joomin Lee, Su-Hyeong Kim, Anuradha Sehrawat, Julie A. Arlotti, Sruti Sajjan Shiva, Rohit Bhargava, Shivendra V. Singh. Prevention of mammary carcinogenesis and pulmonary metastasis by Ayurvedic medicine constituent withaferin A in a clinically-relevant transgenic mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 175. doi:10.1158/1538-7445.AM2013-175