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Pregnancy-Induced Changes in Breast Cancer Risk

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Abstract

Breast cancer is the malignant disease most frequently diagnosed in women of all races and nationalities. Since the 1970s the worldwide incidence of this disease has increased 30–40% in postmenopausal women, in whom, paradoxically, the risk of developing breast cancer is significantly reduced by an early first full term pregnancy (FTP) as compared to nulliparous and late parous women. Although the cause of breast cancer is not known, the mechanisms mediating the protection conferred by an early FTP have been identified to reside in the breast itself, and to be modulated by endogenous and environmental exposures that might negatively affect this organ during specific windows in its development that extend from prenatal life until the first pregnancy. Soon after conception the embryo initiates the production of human chorionic gonadotropin (hCG), the glycoprotein hormone that is diagnostic of pregnancy. HCG in conjunction with ovarian steroid hormones primes the hypothalamic neuroendocrine system for maintaining the pregnancy. Higher levels of hCG during the first trimester of pregnancy have been associated with a reduction in maternal breast cancer incidence after age 50. In preclinical studies it has been demonstrated that both FTP and hCG treatment of virgin rats prevent the development of chemically-induced mammary tumors, a phenomenon mediated by the differentiation of the mammary gland epithelial cells prior to carcinogen exposure. Complete differentiation proceeds through complex morphological, physiological and molecular changes that occur during pregnancy and lactation, that ultimately result in increased DNA repair capabilities of the mammary epithelium, activation of genes controlling differentiation and programmed cell death and imprinting in the breast epithelium a specific and permanent genomic signature of pregnancy. This signature is indicative of a reduced breast cancer risk and serves as a molecular biomarker of differentiation for evaluating the potential use of chemopreventive agents.

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Abbreviations

AB:

alveolar bud

DMBA:

7,12-dimethylbenz(a)anthracene

ER:

estrogen receptor

FTP:

full term pregnancy

GEM:

Genetically engineered mice

GnRH:

gonadotropin releasing hormone

GO:

Gene Ontology

HCG:

human chorionic gonadotropin

hGH:

human growth hormone

HPG:

hypothalamic–pituitary–gonadal axis

hPL:

human placental lactogen

HPW:

hormonal prevention window

HRSW:

high risk susceptibility window

IC:

intermediate cell

ICE:

interleukin 1beta-converting enzyme

IDP:

intraductal proliferation

LH:

luteinizing hormone

Lob:

lobule

MCSC:

mammary cancer stem cell

MFR:

monthly fecundity rate

PAH:

polycyclic aromatic hydrocarbons

POA:

preoptic area

PMSC:

progenitor mammary stem cells

PR:

progesterone receptor

PRL:

prolactin

rCG:

rat chorionic gonadotropin

rPL:

rat placental lactogen

TEBs:

terminal end buds

TRPM2:

testosterone repressed prostate message 2

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Russo, I.H., Russo, J. Pregnancy-Induced Changes in Breast Cancer Risk. J Mammary Gland Biol Neoplasia 16, 221–233 (2011). https://doi.org/10.1007/s10911-011-9228-y

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