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Exposures to Synthetic Estrogens at Different Times During the Life, and Their Effect on Breast Cancer Risk

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Abstract

Women are using estrogens for many purposes, such as to prevent pregnancy or miscarriage, or to treat menopausal symptoms. Estrogens also have been used to treat breast cancer which seems puzzling, since there is convincing evidence to support a link between high lifetime estrogen exposure and increased breast cancer risk. In this review, we discuss the findings that maternal exposure to the synthetic estrogen diethylstilbestrol during pregnancy increases breast cancer risk in both exposed mothers and their daughters. In addition, we review data regarding the use of estrogens in oral contraceptives and as postmenopausal hormone therapy and discuss the opposing effects on breast cancer risk based upon timing of exposure. We place particular emphasis on studies investigating how maternal estrogenic exposures during pregnancy increase breast cancer risk among daughters. New data suggest that these exposures induce epigenetic modifications in the mammary gland and germ cells, thereby causing an inheritable increase in breast cancer risk for multiple generations.

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Abbreviations

BIRADS:

breast imaging reporting and data system

BMP4:

bone morphogenic protein 4

CCA:

clear cell adenocarcinoma

CEE :

conjugated equine estrogens

DES:

diethylstilbestrol

DMBA:

9,12-dimethylbenz[a]anthracene

DNMT:

DNA methyltransferase

E2:

17-β estradiol

EE2:

ethinyl estradiol

EPIC:

european prospective investigation into cancer and nutrition

ERα :

estrogen receptor α

ERβ:

estrogen receptor β

EZH2:

enhancer of zeste-2

FGF:

fibroblast growth factors

HF:

high fat

HDAC:

histone deacetylase

HT:

hormone therapy

hESC:

human embryonic stem cells

IGF:

insulin-like growth factor

MNU:

methylnitrosourea

NSABP:

national surgical adjuvant breast and bowel project

MPA:

medroxyprogesterone acetate

miRNA:

microRNAs

OC:

oral contraceptives

PTHrP:

parathyroid hormone-related protein

PTH1R:

parathyroid hormone 1 receptor

PcTG :

polycomb target genes

P:

progesterone

RPFNA:

random periareolar fine-needle aspiration

STAR:

study of tamoxifen and raloxifene

TAM:

tamoxifen

TDLU:

terminal ductal lobular unit

TEB:

terminal end buds

TSG:

tumor suppressor gene

WHI:

women’s health initiative

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Disclosure

L. Hilakivi-Clarke has served as an expert witness in a case concerning breast cancer risk in daughters of DES-exposed mothers on behalf of the plaintiffs

Funding support

This study was supported by the National Cancer Institute (R01 CA164384-01A1, U54 CA100970, U54CA149147, and P30 CA051668)

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Authors and Affiliations

  1. Department of Oncology, Georgetown University, Washington, DC, USA

    Leena Hilakivi-Clarke, Sonia de Assis & Anni Warri

  2. Institute of Biomedicine, University of Turku Medical Faculty, Turku, Finland

    Anni Warri

  3. Georgetown University Medical Center, Research Building, Room E407, 3970 Reservoir Road, NW, Washington, DC, 20057, USA

    Leena Hilakivi-Clarke

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  1. Leena Hilakivi-Clarke
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Correspondence to Leena Hilakivi-Clarke.

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Hilakivi-Clarke, L., de Assis, S. & Warri, A. Exposures to Synthetic Estrogens at Different Times During the Life, and Their Effect on Breast Cancer Risk. J Mammary Gland Biol Neoplasia 18, 25–42 (2013). https://doi.org/10.1007/s10911-013-9274-8

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