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Role of differentiation in carcinogenesis and cancer prevention
Breast Cancer Research volume 5, Article number: 31 (2003)
Ductal carcinoma is the malignant disease most frequently diagnosed in American women. This cancer type originates in Stem Cells 1, epithelial cells that are the main components of the undifferentiated mammary gland. The susceptibility of Stem Cells 1 to become transformed has been attributed to their high rate of cell proliferation, their ability to bind and activate the carcinogen and their low DNA reparative activity. Epidemiological evidence indicates that a woman's lifetime risk for developing breast cancer is decreased by a full-term pregnancy at a young age. The protection conferred by pregnancy is the result of the differentiation of the organ. The reproduction of the hormonal milieu of an early full-term pregnancy by administration of human chorionic gonadotropin (hCG) to virgin rats induces lobular development, completing the cycle of differentiation of the breast that converts the highly susceptible Stem Cell 1 into a resistant Stem Cell 2 through a process of induction of a specific genomic signature in the mammary epithelium. Both pregnancy and hCG exert a protective effect on the mammary gland by reducing the incidence of 7,12-dimethyl-benz(a)anthracene (DMBA)-induced carcinomas. Although differentiation significantly reduces cell proliferation in the mammary epithelium, the differentiated Stem Cell 2 remains capable of responding with proliferation to given stimuli, such as a new pregnancy; it is also capable of metabolizing the carcinogen and of repairing DNA damage more efficiently than the Stem Cell 1. The basic biological concept is that the conversion of the susceptible Stem Cell 1 to a refractory Stem Cell 2 after pregnancy or hCG treatment of virgin rats results from the differentiation of the mammary gland, a phenomenon manifested at morphological, cell kinetic and functional levels. Morphological changes consist of a progressive branching of the mammary parenchyma and lobule formation, which in turn result in a reduction in cell growth fraction and lengthening of the cell cycle. The functional changes comprise increased synthesis of inhibin, β-casein and other milk-related bioactive peptides. In addition, pregnancy or hCG also increases the expression of programmed cell death genes, including TRPM2, ICE, p53, c-myc, and bcl-XS, inducing as well apoptosis, and downregulation of cyclins. Programmed cell death genes were activated through a p53-dependent process, modulated by c-myc, and with partial dependence on the bcl-2 family-related genes. Data generated using the cDNA microarray techniques have allowed us to demonstrated that while lobular development regressed after the cessation of pregnancy or hormone administration, programmed cell death genes remained activated, and new sets of genes reached a peak of maximal expression while others became downregulated, creating a genomic signature that is specific for both pregnancy and hCG treatment, but significantly different from those induced by the ovarian steroid hormones estrogen and progesterone. These mechanisms play a role in the protection exerted by hCG from chemically induced carcinogenesis, and might be even involved in the lifetime reduction in breast cancer risk induced in women by full-term and multiple pregnancies. In addition, hCG inhibits the progression of DMBA-induced mammary tumors on the early phases of tumor progression (i.e. intraductal proliferation, in situ carcinomas and invasive carcinomas). These observations led us to infer that hCG, like pregnancy, induces early genomic changes that lead the mammary gland to full differentiation, and that these changes result in a permanently imprinted genomic signature that regulates the long-lasting refractoriness of the mammary gland to carcinogenesis. The permanence of these changes makes them ideal surrogate markers of hCG effect in the evaluation of this hormone as a breast cancer preventive agent.
This work has been supported by National Institutes of Health grants RO1-CA64896, R01 CA67238, R21 CA87230, RO1 CA93599, DAMD17-99-9182, DAMD 17-00-1-0249, DAMD 17-00-1-0247, and DAMD 17-00-2-1-0384.
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Russo, J., Russo, I. Role of differentiation in carcinogenesis and cancer prevention. Breast Cancer Res 5, 31 (2003). https://0-doi-org.brum.beds.ac.uk/10.1186/bcr690
- Mammary Gland
- Genomic Signature
- Programme Cell Death Gene