Local versus systemically mediated effects of estrogen on normal mammary epithelial cell deoxyribonucleic acid synthesis.

While it has been shown that estrogen promotes mammary gland growth in vivo, it has not been demonstrated if estrogen acts locally in the mammary gland to produce a mitogenic effect in the epithelial cells or if the mitogenic effect is mediated systemically. The purpose of this study was to distinguish between local vs. systemically mediated modes of estrogen action in normal mammary glands of both immature 5-week-old and sexually mature 10-week-old mice. Elvax 40P, noninflammatory, easily manipulated implant material, was combined with 17 beta-estradiol and placed either directly into the mammary gland to elicit a localized effect or implanted sc to produce a systemic effect. The effect of estrogen on epithelial cell proliferation was assessed by its effect on mammary gland morphology from whole mount examinations and on DNA synthesis by DNA histoautoradiography. The effects of implant location and estrogen dose on mammary and uterine progesterone receptor (PgR) concentrations were also analyzed. The results indicate that estrogen can act locally to stimulate increased epithelial DNA synthesis and an increase in end-bud size in the immature mammary gland. By contrast, no localized effect of estrogen could be demonstrated in the mature mammary gland; it appears that increased epithelial DNA synthesis and ductal side-branching are systematically mediated effects of estrogen. On the other hand, in the case of PgR regulation, estrogen can act locally to increase receptor concentration in the adult gland. In contrast, in the immature mammary gland only low levels of PgR were detectable, and they could not be increased by any method of estrogen treatment. Thus, these results demonstrate that estrogen can act either locally or systemically to produce mitogenic effects on mammary epithelium. However, the age and/or developmental stage of the target tissue are important factors that determine the hormonal responsiveness of normal tissue and which mode (local vs. systemic) of estrogen action will be operative.