Cytokine signalling in mammary gland development

Mammary gland development occurs in three distinct stages during the lifetime of the female mammal: in embryonic, pubertal and reproductive life. At each of these developmental stages, different signalling molecules induce changes in both the epithelium and the surrounding stroma. However, it is during pregnancy that the most dramatic changes occur, resulting in a massive increase in the number of epithelial cells and in their function. Pregnancy initiates the development of a new epithelial lineage, the alveolar cells, which form the milk-producing lobuloalveolar structures. These cells become redundant at the end of lactation and are removed in an exquisitely controlled process of tissue remodelling coupled with extensive cell death. All of these events require not only steroid hormones but also sequential signalling by cytokines. A recent surprising discovery was that the signalling pathways and cytokines that regulate lineage determination in T helper cells are also involved in mammary gland development during pregnancy.     

Primary lymphoproliferative lesions of the mammary gland

Occasionally, the breast is the site of a localized, primary lymphoma with no evidence of concurrent widespread or preceding extramammary disease at the time of presentation (Stage I) or within 1-6 months thereafter. Cases with concurrent or subsequent ipsilateral axillary node involvement (Stage II) have also been accepted as primary lymphomas by some investigators, and such involvement has been observed in 48.5% of the cases. More commonly, the breast is involved secondarily by widespread lymphoma. Patients with PML range in age from 9 to 90 years, with a median ranging from 55 to 68 years in various reports. Clinical symptomatology varies considerably. Most patients present with a breast mass or complain of pain. About 10% of the patients may have night sweats, fever, and weight loss. Occasionally multiple nodules may be present within the breast. These nodules can cause overlying skin changes similar to those associated with carcinoma and may even involve the nipple. Mammographically, lymphomas form relatively circumscribed masses, focal or diffuse thickening and densities, and discrete nodules with irregular margins; typically, they lack calcification and retraction.     

Dehydroepiandrosterone,androgens and the mammary gland

Mainly through the transformation of dehydroepiandrosterone (DHEA) into androgens in peripheral tissues by intracrine mechanisms, women synthesize at least two-thirds of the androgens found in men. Such data strongly suggest that androgens exert very important but so far underestimated physiological functions in women, including in the breast. In fact, the mammary gland possesses all the enzymatic machinery required to transform DHEA into both androgens and estrogens, although androgens are the predominant steroids synthesized from DHEA in the mammary gland. Early clinical studies have shown beneficial effects of androgens on breast cancer which are comparable to those observed with other hormonal therapies. In fact, a long series of preclinical and clinical data clearly indicate that proliferation of both the normal mammary gland and breast cancer results from the balance between the stimulatory effect of estrogens and the inhibitory effect of androgens. Moreover, the data showing the additive inhibitory effects of antiestrogens and androgens suggest that taking advantage of the inhibitory effect of androgens on breast cancer proliferation could well improve the efficacy of the currently used estrogen deprivation therapies for the treatment and prevention of breast cancer, the best and most physiological candidate being DHEA that limits the androgenic exposure to the tissues which possess the required enzymatic intracrine machinery.