Pregnancy-Induced Changes in Breast Cancer Risk

Article

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.

Keywords

Breast cancer prevention Early pregnancy Human chorionic gonadotropin Late pregnancy Breast cancer risk Hypothalamic aging Hypothalamic–pituitary–gonadal axis 

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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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Molecular Endocrinology Section, Breast Cancer Research LaboratoryFox Chase Cancer CenterPhiladelphiaUSA
  2. 2.Breast Cancer Research LaboratoryFox Chase Cancer CenterPhiladelphiaUSA

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