Role of Endogenous Hormones in Breast Developmentand Carcinogenesis

Epidemiologic studies have shown that hormones play an important role in the pathogenesis of breast cancer. In general, exposure to hormones is believed to increase risk of breast cancer. Early menarche, late menopause, nulliparity, and delayed child bearing are all associated with increased breast cancer risk. Many studies on the biology of and the role of hormones on breast development have been performed on rodents. Estrogen and progesterone have a profound role in breast development, but there is an important role for pituitary hormones because ovarian hormones fail to promote proliferation and/or differentiation in hypophysectomized animals.13 To understand the role of hormones on breast cancer, an understanding ofthe role ofhormones in breast development and differentiation is helpful.

The mammary gland is composed of epithelial and mesenchymal components. The major functional unit of the mammary gland is the terminal ductal lobular unit. This terminal lobular structure is composed of the terminal breast ducts and the blind-ended ductules at the end ofthese terminal ducts. Most breast tumors arise in the terminal ductal lobular unit14 And retain some of the morphologic and molecular biologic features of those cells. The ductal system is lined by luminal epithelial cells surrounded by myoepithelial cells that are in direct contact with the basement membrane. The majority of proliferating cells are found within the luminal epithelium,14 and it is these dividing cells that are most prone to malignant transformation. Their growth is stimulated by the interaction of hormones with hormone receptors, especially ERs and progesterone receptors (PRs).

There are two types of ERs, the classical estrogen receptor (ERa) and the more recently identified ERp. ERa is expressed in 15% to 30% of normal luminal epithelial cells and not at all in any of the other cell types.1516 ERp is present in most luminal epithelium and myoepithelial cells as well as in some fibroblasts, endothelial cells, and lymphocytes.17 Data suggest that ERa is the key mediator of the growth stimulatory effects of estrogen on the mammary gland.14 ERa is expressed in infant, pubertal, and cycling adult breast.18

There are two types of PRs, PRA and PRB. PRA and PRB are expressed similarly to ERa in that they are expressed in a minority of cells throughout the luminal epithelium. They are concentrated in the terminal bud cells. They are not expressed in the myoepithelial or stromal cells.15,19,20 PR expression is induced by estrogens at the transcriptional level and decreased by progestins at both the transcriptional and translational levels.21 All the cells that express PR also contain ERa.15

Studies have shown that, in the normal human breast, proliferating cells contain neither ERa nor PRs.15 The cells that contain these receptors are separate from, but adjacent to, the proliferating cells. This suggests that estrogen and/or progesterone controls proliferation of luminal epithelial cells indirectly through paracrine growth factors secreted by the epithelium.14

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  • Category: Women's diseases