Genomic signature and susceptibility to breast cancer

Early parity is associated with a pronounced decrease in the risk of breast cancer, and additional live births reduce the risk even move. The protection afforded by early full-term pregnancy in women can be explained by the higher degree of differentiation of the mammary gland, which eliminates type 1 stem cells and creates a second type of stem cell (stem cell 2) that is able to metabolize carcinogens and repair DNA damage more efficiently than cells of the nulliparous breast. All though differentiation significantly reduces cell proliferation in the mammary gland, the epithelium remains capable of responding to a given stimulus, such as a new pregnancy. Under these circumstances, the cells that are stimulated to proliferate are derived from structures that have already been primed by the first cycle of differentiation. However, if the shift from stem cell 1 to stem cell 2 has not been completed, a sufficiently powerful carcinogenic stimulus may overburden the system, and successfully initiate a neoplastic process. Incomplete differentiation of this type may explain the development of breast cancer after a late first full-term pregnancy. The finding that differentiation is a powerful inhibitor of cancer initiation provides a strong rationale for pursuing the identification of the genes that control this process.

Molecular biology and gynecology: CD 36 and its interactions with tamoxifen

Tamoxifen (TAM) is an antiestrogenic drug widely used in breast cancer treatment. By using the Differential Display technique in normal and malignant breast tissues, before and during TAM therapy, we were able to demonstrate that expression of the CD36 gene is down-regulated by this drug. CD36 is a cell-surface glycoprotein that acts as a receptor for thrombospondin-1, oxidized-LDL and collagens type I and IV. Thrombospondin-1 is involved in invasion, metastasis and angiogenesis and therefore the down-regulation of CD36 induced by TAM, might correspond to an alternative mechanism of action of this drug. CD36 is also one of the receptors for the oxidized-LDL which in turn is involved in pathogenesis of arteriosclerosis; thus the down-regulation of CD36 during TAM might explain the at least in part the lower levels of myocardial infarction during its use.

Differentiation and breast cancer

The mammary gland is an organ whose size, shape and function undergo fundamental changes during the various phases of a woman's growth. Although the development of the mammary gland begins during infancy, the most dramatic changes occur with the initiation of puberty. Pregnancy and lactation complete the functional development of the organ, which regresses during menopause. Epidemiological and experimental studies have demonstrated that certain hormonal influences, especially those related to reproduction, modify the risk of developing breast cancer. Thus, a full term pregnancy completed before the age of 24 years significantly reduces the lifetime incidence of breast cancer. Although the mechanism through which pregnancy protects the breast from breast cancer has not been clearly established, experimental models of mammary carcinogenesis have allowed researchers to determine that pregnancy inhibits the initiation of the neoplastic process through the induction of a complete differentiation of the mammary gland. This process activates specific genes, which in turn modify the response of the organ to ulterior hormonal changes. It is postulated that the same mechanism might be responsible for the protective effect of a woman's early first full term pregnancy. The greater incidence of breast cancer observed in nulliparous women correlates well with the greater susceptibility of the virgin rat to develop mammary carcinomas when exposed to chemical carcinogens. The successful induction of malignant transformation in the virgin animal mammary epithelium is due to the presence of undifferentiated structures with a high rate of cell proliferation. These structures are eliminated by pregnancy. The breast of nulliparous women retains those undifferentiated structures, which increase the predisposition of the organ to undergo malignant transformation, which will manifest itself clinically several years after its initiation. The correlation of human epidemiological, clinical and experimental data with those data obtained in rodent experimental models lends support to this hypothesis.