title: Mechanisms of hormonal prevention of breast cancer.
abstract: Reproductive history is a consistent risk factor for human breast cancer. Epidemiological studies have repeatedly demonstrated that early age of first pregnancy is a strong protective factor against breast cancer and provides a physiologically operative model to achieve a practical mode of prevention. In rodents, the effects of full-term pregnancy can be mimicked by a three-week exposure to low doses of estrogen and progesterone. Neither hormone alone is sufficient to induce protection. The cellular and molecular mechanisms that underlie hormone-induced refractoriness are largely unresolved. Our recent studies have demonstrated that an early cellular response that is altered in hormone-treated mammary cells is the initial proliferative burst induced by the chemical carcinogen methylnitrosourea. The decrease in proliferation is also accompanied by a decrease in the ability of estrogen receptor-positive cells to proliferate. RNA expression of several mammary cell-cycle-related genes is not altered in hormone-treated mice; however, immunohistochemical assays demonstrate that the protein level and nuclear compartmentalization of the p53 tumor suppressor gene are markedly upregulated as a consequence of hormone treatment. These results support the hypothesis that hormone stimulation, at a critical period in mammary development, results in cells with persistent changes in the intracellular regulatory loops governing proliferation and response to DNA damage. A corollary to this hypothesis is that the genes affected by estrogen and progesterone are independent of alveolar differentiation-specific genes. Suppressive subtractive hybridization-PCR methods have identified several genes that are differentially expressed as a consequence of prior estrogen and progesterone treatment. Future experiments are aimed at determining the mechanisms of hormone-induced upregulation of p53 protein expression as part of the overall goal of identifying and functionally characterizing the genes responsible for the refractory phenotype.
authors.affiliation: Department of Molecularand Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. dmedina@bcm.tmc.edu
authors.forename: D
authors.initials: D
authors.lastname: Medina
authors.forename: L
authors.initials: L
authors.lastname: Sivaraman
authors.forename: S G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.forename: O
authors.initials: O
authors.lastname: Conneely
authors.forename: M
authors.initials: M
authors.lastname: Ginger
authors.forename: J
authors.initials: J
authors.lastname: Rosen
authors.forename: B W
authors.initials: BW
authors.lastname: Omalle
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics / Q000517:prevention & control; D000818:Animals; D001943:Breast Neoplasms / Q000453:epidemiology / Q000517:prevention & control*; D002455:Cell Division; D004249:DNA Damage; D004958:Estradiol / Q000008:administration & dosage / Q000627:therapeutic use*; D004967:Estrogens / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D016158:Genes, p53; D006801:Humans; D008321:Mammary Glands, Animal / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D008770:Methylnitrosourea; D051379:Mice; D008815:Mice, Inbred Strains; D009376:Neoplasms, Hormone-Dependent / Q000453:epidemiology / Q000517:prevention & control; D011247:Pregnancy; D011374:Progesterone / Q000008:administration & dosage / Q000502:physiology / Q000627:therapeutic use*; D051381:Rats; D011920:Rats, Inbred WF; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism; D017584:Reproductive History; D012307:Risk Factors
chemical_list: D004967:Estrogens; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011374:Progesterone; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene; D008770:Methylnitrosourea