Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogen-stimulated growth of the malignant human endometrium can be balanced by the differentiating properties of progesterone. To study the molecular basis behind this, gene expression profiling was performed using complementary DNA microarray analysis. In this study, the human endometrial cancer cell lines ECC-1 and PRAB-36 were used as models. The ECC-1 cell line, which expresses high levels of estrogen receptor alpha and is stimulated in growth by estrogens, was used to study estrogen regulation of gene expression. The Ishikawa sub-cell line PRAB-36, expressing both PRA and PRB, progesterone receptor isoforms, and inhibited in growth by progestagens, was used to study progesterone regulation of gene expression. Using these two well-differentiated human endometrial cancer cell lines, 148 estrogen- and 148 progesterone-regulated genes were identified. After functional classification, the estrogen- and progesterone-regulated genes could be categorized in different biologically relevant groups. Within the group of "cell growth and/or maintenance," 81 genes were clustered, from which a number of genes could be involved in arranging the cross talk that exists between estrogen and progesterone signaling. On the basis of analysis of the current findings, it is hypothesized that cross talk between estrogen and progestagen signaling does not occur by counterregulation of single genes, but rather at the level of differential regulation of different genes within the same functional families.
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PMID:Growth regulation and transcriptional activities of estrogen and progesterone in human endometrial cancer cells. 1644 20

The possible role of specific progesterone receptor (PR) isoforms (PRA and PRB) as predictive factors in endometrial carcinoma is unclear. The present study was undertaken to evaluate the clinical significance of intratumoral PR isoform status in patients with endometrioid endometrial carcinoma. We studied 103 cases of endometrioid endometrial carcinoma using immunohistochemistry. We correlated the findings with various clinicopathological parameters of the patients. PRA and PRB immunoreactivity was detected in 51/103 (48.5%) and 79/103 (76.7%) of carcinoma cases, respectively. A significant positive correlation was detected between the status of PRB immunoreactivity and the amount of PRB mRNA by real-time reverse transcription-polymerase chain reaction (P = 0.012). PR isoform expression was significantly lower in the cases with higher histological grade (P = 0.0001 and P = 0.002, for PRA and PRB, respectively). Cases that were negative for either one or both PR isoforms were significantly associated with shorter disease-free and overall survival of the patients. The absence of either one or both of these two PR isoforms was detected in all nine patients who died (100.0%), whereas the absence of these immunoreactivities was detected only in 43 of 94 (45.7%) patients who had lived during the same period. In addition, multivariate analysis demonstrated that an absence of PRA immunoreactivity was an independent risk factor in disease-free survival of the patients (P = 0.0258). The results of our study demonstrated that loss or absence of PR isoform expression determined by immunohistochemistry could become an important prognostic indicator in patients with endometrioid endometrial carcinoma.
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PMID:Progesterone receptor isoforms as a prognostic marker in human endometrial carcinoma. 1699 16

In many type I endometrial cancers, the PTEN gene is inactivated, which ultimately leads to constitutively active Akt and the inhibition of Forkhead box O1 (FOXO1), a member of the FOXO subfamily of Forkhead/winged helix family of transcription factors. The expression, regulation, and function of FOXO1 in endometrial cancer were investigated in this study. Immunohistochemical analysis of 49 endometrial tumor tissues revealed a decrease of FOXO1 expression in 95.9% of the cases compared with the expression in normal endometrium. In four different endometrial cancer cell lines (ECC1, Hec1B, Ishikawa, and RL95), FOXO1 mRNA was expressed at similar levels; however, protein levels were low or undetectable in Ecc1, Ishikawa, and RL95 cells. Using small interfering RNA technology, we demonstrated that the low levels of FOXO1 protein were due to the involvement of Skp2, an oncogenic subunit of the Skp1/Cul1/F-box protein ubiquitin complex, given that silencing Skp2 increased FOXO1 protein expression in Ishikawa cells. Inhibition of Akt in Ishikawa cells also increased nuclear FOXO1 protein levels. Additionally, progestins increased FOXO1 protein levels, specifically through progesterone receptor B (PRB) as determined by using stably transfected PRA-specific and PRB-specific Ishikawa cell lines. Finally, overexpression of triple mutant (Tm) FOXO1 in the PR-specific Ishikawa cell lines caused cell cycle arrest and significantly decreased proliferation in the presence and absence of the progestin, R5020. Furthermore, TmFOXO1 overexpression induced apoptosis in PRB-specific cells in the presence and absence of ligand. Taken together, these data provide insight into the phosphoinositide-3-kinase/Akt/FOXO pathway for the determination of progestin responsiveness and the development of alternate therapies for endometrial cancer.
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PMID:The regulation and function of the forkhead transcription factor, Forkhead box O1, is dependent on the progesterone receptor in endometrial carcinoma. 1809 67

Progesterone is a key hormone in the regulation of uterine function. In the normal physiological context, progesterone is primarily involved in remodeling of the endometrium and maintaining a quiescent myometrium. When pathologies of the uterus develop, specifically, endometrial cancer and uterine leiomyoma, response to progesterone is usually altered. Progesterone acts through mainly two isoforms of the progesterone receptor (PR), PRA and PRB which have been reported to exhibit different transcriptional activities. Studies examining the expression and function of the PRs in the normal endometrium and myometrium as well as in endometrial cancer and uterine leiomyoma are summarized here. The clinical use of progestins and the transcriptional activity of the PR on genes specific to endometrial cancer and leiomyoma are described. An increased understanding of the differential expression of PRs and response to progesterone in these two diseases is critical in order to develop more efficient and targeted therapies.
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PMID:Progesterone receptor action in leiomyoma and endometrial cancer. 2037 1

Progesterone is a growth inhibitory hormone in the endometrium. While progestins can be used for the treatment of well-differentiated endometrial cancers, resistance to progestin therapy occurs for reasons that remain unclear. We have previously demonstrated that progesterone receptors (PR) A and B differentially regulate apoptosis in response to overexpression of the forkhead transcription factor, FOXO1. In this study, we further examined the PR-isoform-dependent cellular response to the AKT pathway. Treatment of PRA and PRB-expressing Ishikawa cells (PRA14, PRB23), with an AKT inhibitor API-59CJ-OMe (API-59) promoted apoptosis in the presence and absence of the ligand, R5020 preferentially in PRA14 cells. Upon PR knockdown using small interfering RNA, an increase in apoptosis was observed in PRB23 cells treated with API-59 with or without R5020 while there was no influence in PRA14 cells. Using an apoptosis-focused real-time PCR array, genes regulated by API-59 and R5020 were identified both common and unique to PRA14 and PRB23 cells. BIRC3 was identified as the only gene regulated by R5020 which occurred only in PRB cells. Knockdown of BIRC3 in PRB23 cells promoted a decrease in cell viability in response to API-59 + R5020. Furthermore, the important role of inhibitors of apoptosis (IAPs) in the PRB23 cells to promote cell survival was demonstrated using an antagonist to IAPs, a second mitochondria-derived activator of caspase (Smac also known as DIABLO) mimetic. Treatment of PRB23 cells with Smac mimetic increased apoptosis in response to API-59 + R5020. In summary, our findings indicate a mechanism by which PRB can promote cell survival in the setting of high AKT activity in endometrial cancer cells.
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PMID:Progesterone receptor-B induction of BIRC3 protects endometrial cancer cells from AP1-59-mediated apoptosis. 2176 Aug 55


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