The contribution of pituitary gland hormones to mammary gland tumorigenesis was revealed more than years ago when breast cancer was treated by hypophysectomy. The regression of breast cancers resistant to antiestrogen therapy following hypophysectomy and the fact that PRL restored vulnerability to mammary tumorigenesis in hypophysectomized rats pointed to PRL as the putative pituitary hormone essential for mammary tumor development.The participation of PRL in mammary cancer has been established in rodents, where Fosfomycin calcium hyperprolactinemia or PRL treatment increases the number of spontaneous mammary tumors and susceptibility to mammary carcinogens, while decreasing systemic PRL inhibits mammary tumor growth. Furthermore, immunoneutralization of PRL inhibits the development of carcinogeninduced mammary tumors, and lack of PRL receptors reduces the size of mammary Pentoxifylline neoplastic growths. PRL was initially considered irrelevant due to contrasting data provided by multiple clinical studies. Such variability was recently overcome by large, wellcontrolled studies showing that higher plasma PRL levels signicantly increase the relative risk of developing breast cancer in premenopausal and postmenopausal women. In addition, epidemiological studies support the association of both dopamine antagonists and hyperprolactinemia with increased breast cancer risk. Of importance, however, neoplastic breast tissue synthesizes PRL, which is unaffected by dopamine, and it is recognized that PRL acts partly as an autocrineparacrine promoter of mammary tumor growth. Up to of breast tumors express PRL receptors, and receptor levels are higher in neoplastic tissue than in adjacent normal tissue, and it promotes the expression of VEGF in mammary gland cell lines; thus increased angiogenesis may contribute to the stimulatory action of PRL on breast cancer.Mammary carcinomas in organ culture have diminished ability to generate vasoinhibins from PRL, and hypoxic conditions, mimicking the tumor microenvironment, are associated with reduced secretion of cathepsin D by a cultured pituitary adenoma cell line. Notably, colon cancer cells overexpressing vasoinhibins generate smaller and less vascularized tumors in mice.In addition to PRL, the GHIGFI axis has been shown in recent studies to play a key role in mammary cancer, particularly in animal models. GH restores vulnerability to mammary carcinogens in hypophysectomized rats. Disruption of the GH receptor gene inhibits oncogenedriven mammary tumorigenesis and mice with a liverspecic IGFI gene deletion exhibit low incidence of chemically induced mammary tumors.GH may act as an oncogene, since its expression in the normal human mammary gland increases with the acquisition of proliferative lesions, and the experimental overexpression of GH transforms a human, nontumorigenic mammary epithelial cell line into a tumorigenic, invasive phenotype. In support of angiogenesis being among the tumorigenic effects of GH, receptors for GH are found in endothelial cells of newly formed tumor capillaries, and the overexpression of GH in human mammary carcinoma cells stimulates endothelial cell migration and tube formation in vivo dependent of VEGF. Also, autocrine GH downregulates the production of the antiangiogenic factor thrombospondin. The direct actions of GH in promoting tumor growth may involve crosstalk with the PRL receptor, which binds human GH.By overexpressing receptorspecic ligands it was shown that the PRL receptor, but not the GH receptor, mediates the high incidence of chemically induced mammary tumors in mice.