Progestin effects on cell proliferation pathways in the postmenopausal mammary gland

Breast Cancer Research

William C Dougall¹  Hermina Borgerink³  Li-Ya Huang²  Kathy Rohrbach²  Thomas C Register³  J Mark Cline³  Allison P Jacob¹  Daniel Branstetter²  Charles E Wood³ 

[1] Therapeutic Innovation Unit (TIU), Amgen Inc, Seattle, WA 98119, USA;Department of Pathology, Amgen Inc, Seattle, WA 98119, USA;Department of Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA

关键词: Denosumab;    RANKL;    Gene expression;    Breast cancer;    Tibolone;    Progestin;    Estrogen;    Postmenopausal hormone therapy;   

Others  :  794083
DOI  :  10.1186/bcr3456

 received in 2013-01-29, accepted in 2013-07-22,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Wood et al.; licensee BioMed Central Ltd.

【 图 表 】

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