Progestin effects on cell proliferation pathways in the postmenopausal mammary gland.
BACKGROUND
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.


CONCLUSIONS
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.
Charles E
CE
Wood
Daniel
D
Branstetter
Allison P
AP
Jacob
J Mark
JM
Cline
Thomas C
TC
Register
Kathy
K
Rohrbach
Li-Ya
LY
Huang
Hermina
H
Borgerink
William C
WC
Dougall
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D004847:Epithelial Cells / Q000378:metabolism; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D020249:Hormone Replacement Therapy; D006801:Humans; D007150:Immunohistochemistry; D008252:Macaca fascicularis; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism*; D009652:Norpregnenes / Q000494:pharmacology; D017698:Postmenopause; D011372:Progestins / Q000378:metabolism* / Q000494:pharmacology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D015415:Biomarkers; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D009652:Norpregnenes; D011372:Progestins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011960:Receptors, Estrogen; C027385:tibolone