Estrogen receptor-α positive (ERα+) breast cancer represents 70-80% of newly diagnosed cases. Regrettably, progression of ERα+ breast cancer to anti-estrogen refractory disease in the metastatic setting is a common occurrence. Endocrine resistance mechanisms may differ between subtypes of ERα+ breast cancer and involve both ERα-independent and ERα-dependent forms that remain poorly understood. There is a lack of preclinical human ERα+ breast cancer models that recapitulate progression from localized mammary gland growth to distant metastasis. Xenografts of primary patient-derived ERα+ breast cancer exhibit poor take rate in mice. We have discovered that murine prolactin is a poor agonist and a potent antagonist for human prolactin receptor. To address this problem, we generated human prolactin knock-in mice in the immunodeficient Nod-Scid-IL2Rγ strain that express physiological levels of circulating human prolactin. Prolactin-humanized mice display greatly increased take rate of primary patient-derived xenografts of ERα+ breast cancer. We established a panel of serially transplantable ERα+ lines, several of which spontaneously metastasize to lungs and liver. The distant metastases become anti-estrogen refractory despite continued expression of ERα. Progress with these models will be presented.