Immunomodulatory and transcriptional effects of progesterone through progesterone A and B receptors in Hec50co poorly differentiated endometrial cancer cells.
OBJECTIVE
Derivatives of progesterone, progestins, are used to treat endometrial cancer; however, the pathways activated by the hormone have not been fully investigated. Progesterone acts through two receptor isoforms, progesterone receptors A and B (PRA and PRB), transcription factors that control the expression of downstream genes leading to endometrial differentiation. The purpose of this study was to perform an expression analysis to identify the mechanisms underlying progesterone's growth suppressive and immunomodulatory effects in endometrial cancer.


METHODS
To study the molecular effects of progesterone, PRs were introduced into Hec50co cells. Expression array analyses followed by confirmatory semiquantitive reverse-transcriptase polymerase chain reaction (RT-PCR) experiments were performed.


RESULTS
Expression analysis demonstrated a significant effect of progesterone after 12 hours of treatment on a number of genes, including cell signaling, DNA remodeling, apoptotic, tumor-suppressor, and transcription factors. Of particular interest was the consistent modulation of cytokines, which generally predicted for a powerful anti-inflammatory effect of progesterone through PR. Specifically, pro-inflammatory genes such as TNFalpha, IL-1beta, and MCP-1/MCAF-1 were down-regulated and anti-inflammatory genes such as TRAP1 and SMAD4 were induced.


CONCLUSIONS
We have discovered that progesterone has a modulatory effect on inflammation and many other important cellular functions. These effects likely underlie the inhibitory effects of progesterone on tumor growth and invasion.
Reproductive Molecular Biology Laboratory, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA.
Suzy
S
Davies
Donghai
D
Dai
Douglas M
DM
Wolf
Kimberly K
KK
Leslie
D016207:Cytokines / Q000235:genetics; D016889:Endometrial Neoplasms / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D011980:Receptors, Progesterone / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured
D016207:Cytokines; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B