Abstract
IntroductionMenopausal 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.MethodsOvariectomized 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.ResultsTreatment 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.ConclusionOur 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.
Highlights
Menopausal hormone therapies vary widely in their effects on breast cancer risk, and the mechanisms underlying these differences are unclear
estrogen plus progestin therapy (EPT) elicits distinct effects on global gene expression profiles Global mammary gland expression profiles were evaluated by microarray analysis
Probes for 1,534 different genes were significantly altered at a fold change (FC) more than 1.5 and an adjusted analysis of variance (ANOVA) P < 0.05
Summary
Menopausal hormone therapies vary widely in their effects on breast cancer risk, and the mechanisms underlying these differences are unclear. Subsequent reports noted increased breast cancer mortality for women taking EPT [5] and decreased breast cancer incidence following discontinuation of EPT [6] These results supported prior epidemiologic studies [7,8] but differed from the sister WHI Estrogen-Alone Trial, in which CEE alone did not increase the incidence of invasive breast cancer among women with a prior hysterectomy [9,10]. These studies confirmed that the promotional effects of EPT on certain types of breast cancer were greater than those seen with estrogen alone
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