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Tamoxifen and black cohosh in ACI.COP-Ept2 rat model of breast cancer
While the efficacy of the selective estrogen receptor modulator (SERM) tamoxifen on estrogen responsive breast cancers is undisputable, side effects such as hot flashes can be extremely uncomfortable. After the Women?s Health Initiative results were published, many healthy women turned to black cohosh and other alternatives to hormone replacement therapy for alleviation of menopausal symptoms. Black cohosh could be beneficial to women with or recovering from breast cancer in alleviating hot flashes induced by a SERM. However, its safety in this population is unknown, and its effect on mammary cancer in vivo has not previously been investigated. We propose to use a new and highly relevant rodent model of breast cancer, ACI.COP-Ept2 to establish not only if BCE fails to promote cancer progression, but also if it inhibits cancer progression. ACI rat mammary tumors have important similarities to human breast cancer. First, tumors in ACI rats are induced by estradiol. Human breast cancer risk is associated with lifelong estrogen exposure. The ability of estradiol to induce tumors in ACI rats makes this model particularly relevant to human breast cancer. Second, ACI rat mammary tumors are estrogen receptor positive and respond to the antiestrogen tamoxifen, similar to the majority of human breast cancers. To the best of our knowledge, this is the only rodent model of breast cancer in which tumors are induced by estradiol and respond to antiestrogens; however, its use has been hindered by the propensity of ACI rats to develop pituitary tumors. A new ACI strain, ACI.COP-Ept2, still develops mammary tumors, but with reduced pituitary hyperplasia and pituitary tumors. Objective/Hypothesis. Our overall objective is to characterize the response of ACI.COP-Ept2 mammary tumors to tamoxifen and black cohosh extract (BCE). Our first hypothesis is that tamoxifen and BCE will shrink estradiol-induced tumors in ACI.COP-Ept2 rats compared to controls. Our second hypothesis is that BCE + tamoxifen will inhibit tumor growth more than either agent alone. Our final hypothesis is that inhibition of tumors by tamoxifen and BCE is mediated through the induction of apoptosis. Specific Aims. Aim 1 will characterize the response of ACI.COP-Ept2 mammary tumors to tamoxifen and BCE. Aim 2 will determine if BCE interacts with tamoxifen to inhibit tumor incidence or growth. Aim 3 will assess markers of proliferation and apoptosis in tumors from Aims 1 and 2. Study Design. ACI.COP-Ept2 rats will be treated with estradiol to induce tumors, and with tamoxifen and/or BCE. Tumors will be monitored, and proliferative and apoptotic indices determined. Potential Outcomes and Benefits. This study will determine whether black cohosh promotes, inhibits, or does not affect breast cancer progression. If black cohosh inhibits or does not promote breast cancer in this model, it may be a safe therapy for hot flashes in the population of women suffering tamoxifen-induced hot flashes.
Black cohosh is an herb which was used by Native Americans to treat a range of medical conditions including menstrual irregularities. Its use was adopted by colonists and incorporated into several patent medicines, including the popular "Lydia E. Pinkham's Vegetable Compound" for rheumatic and gynecologic symptoms. Modern clinical research has focused on the use of black cohosh extracts (BCE) in the treatment of menopause. BCE successfully alleviated hot flashes and other symptoms of menopause in 11 published clinical trials since 1987. Hot flashes are experienced by women undergoing menopause, as well as women taking tamoxifen for the treatment of breast cancer. Many menopausal women use hormone replacement therapy (HRT) to alleviate hot flashes. However, HRT is contraindicated for women being treated for breast cancer with tamoxifen or other medications. Black cohosh may offer an alternative for these women, but first its safety for women with breast cancer must be established. To investigate the safety of black cohosh, we propose to use a new rodent model of breast cancer, the ACI.COP-Ept2 rat. We chose this model because mammary tumors in the animals share two important similarities to the majority of human breast cancers: tumors are induced by estrogen, and they express estrogen receptor. The link between life time estrogen exposure and risk of breast cancer in humans is well established. A high percentage of human breast cancers express estrogen receptor, are stimulated to grow by the addition of exogenous estrogen, and respond to the antiestrogen tamoxifen. Women with breast cancer have few options to cope with hot flashes. Studies like this one are important to establish whether black cohosh can safely be used by these women.