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Open Access 01-08-2013 | Research article

Progestin effects on cell proliferation pathways in the postmenopausal mammary gland

Authors: Charles E Wood, Daniel Branstetter, Allison P Jacob, J Mark Cline, Thomas C Register, Kathy Rohrbach, Li-Ya Huang, Hermina Borgerink, William C Dougall

Published in: Breast Cancer Research | Issue 4/2013

Abstract

Introduction

Menopausal hormone therapies vary widely in their effects on breast cancer risk, and the mechanisms underlying these differences are unclear. The primary goals of this study were to characterize the mammary gland transcriptional profile of estrogen + progestin therapy in comparison with estrogen-alone or tibolone and investigate pathways of cell proliferation in a postmenopausal primate model.

Methods

Ovariectomized female cynomolgus macaque monkeys were randomized into the following groups: placebo (Con), oral conjugated equine estrogens (CEE), CEE with medroxyprogesterone acetate (MPA) (CEE + MPA), and tibolone given at a low or high dose (Lo or Hi Tib). All study treatment doses represented human clinical dose equivalents and were administered in the diet over a period of 2 years.

Results

Treatment with CEE + MPA had the greatest effect on global mRNA profiles and markers of mammary gland proliferation compared to CEE or tibolone treatment. Changes in the transcriptional patterns resulting from the addition of MPA to CEE were related to increased growth factors and decreased estrogen receptor (ER) signaling. Specific genes induced by CEE + MPA treatment included key members of prolactin receptor (PRLR)/signal transducer and activator of transcription 5 (STAT5), epidermal growth factor receptor (EGFR), and receptor activator of nuclear factor kappa B (RANK)/receptor activator of nuclear factor kappa B ligand (RANKL) pathways that were highly associated with breast tissue proliferation. In contrast, tibolone did not affect breast tissue proliferation but did elicit a mixed pattern of ER agonist activity.

Conclusion

Our findings indicate that estrogen + progestin therapy results in a distinct molecular profile compared to estrogen-alone or tibolone therapy, including upregulation of key growth factor targets associated with mammary carcinogenesis in mouse models. These changes may contribute to the promotional effects of estrogen + progestin therapy on breast cancer risk.

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Title: Progestin effects on cell proliferation pathways in the postmenopausal mammary gland
Authors: Charles E Wood
Daniel Branstetter
Allison P Jacob
J Mark Cline
Thomas C Register
Kathy Rohrbach
Li-Ya Huang
Hermina Borgerink
William C Dougall
Publication date: 01-08-2013
Publisher: BioMed Central
Published in: Breast Cancer Research / Issue 4/2013
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/bcr3456

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