Prevention of breast cancer is an unmet clinical need. Despite advances in its early detection and improved treatment options, breast cancer remains a significant health problem. In 2020, about 279,100 and 48,530 individuals were expected to be diagnosed with breast cancer and ductal carcinoma in situ, respectively, and 42,690 people were expected to die of breast cancer in the US alone. Chemoprevention of breast cancer is the most effective way of reducing breast cancer deaths in high-risk populations. Studies using selective estrogen receptor (ER) modulators, and aromatase inhibitors, have shown that breast cancer prevention is feasible; but the chemoprevention approach has been met with very limited acceptance, including among at-risk individuals, due to worrisome levels of toxicity and concerns about engendering acquired resistance. Hence, the clinical need for the development of safer breast cancer preventive agents is readily apparent. Alpha-fetoprotein (AFP) is the protein of pregnancy responsible for the decreased breast cancer risk among parous women. Several population studies as well as laboratory studies have indicated that AFP interferes with estrogen-dependent responses, including the growth-promoting effects of estrogen on breast cancer. α-fetoprotein-derived peptide (AFPep), a cyclic, 9-amino acid synthetic peptide is a stable, orally active, non-toxic mimic of the anti-estrogenic active site of AFP that has been under investigation as a potential agent for prevention or therapy of estrogen receptor positive breast cancer. Preclinical study data on AFPep, as reported by the inventors of the agent, have shown antitumor efficacy without overt toxicity. AFPep arrests growth of human breast cancer xenografts in mouse models, including tamoxifen-resistant human breast cancers and inhibits growth of glioblastoma and leiomyomata (uterine fibroids). Importantly, AFPep prevents development of both carcinogen-induced and estrogen-induced breast cancer in rats. AFPep exhibits no toxicity in mice, rats, dogs or primates, even at doses 1000 times that are needed for efficacy which is likely to make AFPep quite acceptable to at-risk individuals in need of a well-tolerated agent that can reduce their risk of acquiring breast cancer. Despite the promising set of preclinical data generated by the agent inventors, however, efficacy nor safety of AFPep has not been confirmed independently. The overarching goal of this study is to evaluate preclinical efficacy of AFPep in preventing ER positive breast cancers in rodent models in direct head-to-head comparison with a low dose tamoxifen regimen.