Potential benefits of estrogens and progestogens an breast cancer

The mammary gland seems to be the only organ that is not fully developed at birth. Estrogens stimulate breast tissue via estrogen receptors (ERs). In the mammary gland, ER-mediated mechanisms have been shown to regulate: vari ous growth factors, such as TGF-alpha and TGF-beta; enzymes, such as cathep sin D and plasminogen-activator; proto-oncogenes, such as c-fos, c-myc and HER-2/neu; cyclines and other regulatory substances that provide signaling systems for cell division and differentiation; other steroid receptors and epidermal growth factor receptors. Estrogen target genes contain estrogen-r esponsive elements. In these genes, transcription will be activated through interaction with the estrogen/ER protein complex. Subsequent activation of proto-oncogenes provides an explanation for the stimulating effect of estr ogens on the glandular breast. Progesterone may be the key in influencing the risk of breast cancer with t he peak of mitotic activity in the breast during the luteal phase of the me nstrual cycle. On the other hand, in human breast cancer cell lines, both p roliferation and inhibition have been observed with various progestational agents. Relevant biological and clinical issues are pregnancy and exposure to exogenous hormones. The intense hormonal stimulation of pregnancy (both estrogen and progesterone) has no adverse impact on the course of breast ca ncer. Pregnancy, with its mammogenetic differentiation, results in the prot ection of this organ from carcinogenesis. Characterization of specific lobu lar morphology serves as an indicator of the level of differentiation achie ved by the organ, and thus provides means to assess the risk of the gland u ndergoing neoplastic transformation when exposed to given agents. Sufficien t evidence exists to indicate the possibility of a slightly increased risk of breast cancer after approximately one decade of postmenopausal estrogen use. A review of the epidemiologic studies of postmenopausal hormone replac ement and the risk of breast cancer fails to provide definitive evidence. R ecent information derives from observations of cellular proliferation, plas ma and tissue estradiol and progesterone receptor levels, and the percentag e of apoptotic epithelial cells in human breast tissue. Several studies sug gest that short-term, continuous combined HRT does not increase breast canc er recurrence or mortality. The participation of sexual hormones in the mammogenetic process during pre gnancy might serve as an intermediate end point in assessing the effectiven ess of hormones as chemopreventive agents. Investigations based on history, and breast morphology, should enable us to select estrogens and progestoge ns for HRT, and adopt optimal therapeutic regimens.