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Progestin effects on cell proliferation pathways in the postmenopausal mammary gland.
- Source :
-
Breast cancer research : BCR [Breast Cancer Res] 2013; Vol. 15 (4), pp. R62. - Publication Year :
- 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.<br />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.<br />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.<br />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.
- Subjects :
- Animals
Biomarkers metabolism
Cell Proliferation drug effects
Cluster Analysis
Epithelial Cells metabolism
Estrogen Receptor Modulators pharmacology
Estrogens metabolism
Estrogens pharmacology
Female
Gene Expression Profiling
Hormone Replacement Therapy
Humans
Immunohistochemistry
Macaca fascicularis
Mammary Glands, Animal drug effects
Norpregnenes pharmacology
Progestins pharmacology
RANK Ligand genetics
RANK Ligand metabolism
Receptor Activator of Nuclear Factor-kappa B genetics
Receptor Activator of Nuclear Factor-kappa B metabolism
Receptors, Estrogen metabolism
Mammary Glands, Animal metabolism
Postmenopause
Progestins metabolism
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1465-542X
- Volume :
- 15
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Breast cancer research : BCR
- Publication Type :
- Academic Journal
- Accession number :
- 23938070
- Full Text :
- https://doi.org/10.1186/bcr3456