Induction of mammary gland development in estrogen receptor-alpha knockoutmice

Mammary glands from the estrogen receptor-a! knockout (alpha ERKO) mouse do not undergo ductal morphogenesis or alveolar development. Disrupted ER alp ha signaling may result in reduced estrogen-responsive gene products in the mammary gland or reduced mammotropic hormones that contribute to the alpha ERKO mammary phenotype. We report that circulating PRL is reduced in the f emale alpha ERKO mouse. Implantation of an age-matched, heterozygous ER alp ha pituitary isograft under the renal capsule of 25-day-old or 12-week-old alpha ERKO mice increased circulating PRL and progesterone levels, and indu ced mammary gland development. Grafted alpha ERKO mice also possessed hyper trophied corpora lutea demonstrating that PRL is luteotropic in the alpha E RKO ovary. By contrast, ovariectomy at the time of pituitary grafting preve nted mammary gland development in alpha ERKO mice despite elevated PRL leve ls. Hormone replacement using pellet implants demonstrated that pharmacolog ical doses of estradiol induced limited mammary ductal elongation, and estr adiol in combination with progesterone stimulated lobuloalveolar developmen t. PRL alone or in combination with progesterone or estradiol did not induc e alpha ERKO mammary growth. Estradiol and progesterone are required for th e structural development of the alpha EBKO mammary gland, and PRL contribut es to this development by inducing ovarian progesterone levels. Therefore, the manifestation of the alpha ERKO mammary phenotype appears due to the la ck of direct estrogen action at the mammary gland and an indirect contribut ory role of estrogen signaling at the hypothalamic/pituitary axis.