Article in press - uncorrected proof Horm Mol Biol Clin Invest 2011;5(3):143–151 2011 by Walter de Gruyter • Berlin • New York. DOI 10.1515/HMBCI.2010.049
Short Review
Sex steroids in uterine endometrial cancers
Jiro Fujimoto* and Eriko Sato Department of Obstetrics and Gynecology, Graduate School of Medicine, Gifu University School of Medicine, Gifu, Japan
Abstract Some uterine endometrial cancers conserve estrogen dependency in advancement. However, the concept of advancement in tumor is complicated, because it involves simple growth in primary tumor and secondary spreading. The expression manner of estrogen receptor alpha exon 5 splicing variant, ER beta, progesterone receptor-A (N-terminus deletion mutant) is associated with metastatic potential in uterine endometrial cancers. Increased estrogen-related receptor alpha expression is related to tumor advancement with the loss of estrogen dependency. Steroid receptor coactivator-3 contributes to tumor progression and can be used as a treatment target for advanced uterine endometrial cancers. Estrogen responsive oncogenes, c-jun and c-Ha-ras, are not modified by progestin in uterine endometrial cancer cells and are considered to be an instinct phenotype as such cancers. By contrast, metastatic potential of estrogen-dependent uterine endometrial cancers can be partially controlled by progestin via metastasis-related genes, E-cadherin/catenins, plasminogen activator inhibitor-1, vascular endothelial growth factor. Thus, sex steroids related phenomena are impressive in the advancement of uterine endometrial cancers. Keywords: c-Ha-ras; c-jun; E-cadherin/catenins; ER beta (ERb); estrogen receptor alpha exon 5 splicing variant (ERaE5SV); estrogen-related receptor alpha (ERRa); plasminogen activator inhibitor (PAI)-1; progesterone receptor (PR)-A; steroid receptor coactivator (SRC)-3; uterine endometrial cancer; vascular endothelial growth factor (VEGF).
Introduction Some uterine endometrial cancers conserve estrogen dependency in advancement. Tumor advancement is not simple and involves simple growth in primary tumor and secondary *Corresponding author: Jiro Fujimoto, MD, PhD, Professor, Department of Obstetrics and Gynecology, Graduate School of Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan Phone: q81-58-230-6349, Fax: q81-58-230-6348, E-mail: [email protected] Received September 22, 2010; accepted September 24, 2010; previously published online March 4, 2011
spreading metastasis with angiogenesis. To understand molecular mechanisms of tumor advancement, the expression manner of estrogen receptor alpha exon 5 splicing variant (ERaE5SV), ER beta (ERb), progesterone receptor (PR)-A, estrogen-related receptor alpha (ERRa) with steroid receptor coactivator (SRC)-3, estrogen responsive genes (oncogenes), c-jun and c-Ha-ras, metastasis-related genes, E-cadherin/catenins and plasminogen activator inhibitor (PAI)-1, and estrogen responsive angiogenic factors, vascular endothelial growth factor (VEGF), was studied.
Estrogen receptor alpha exon 5 splicing variant Among exon splicing variants, only ERaE5SV (Figure 1) is transcriptionally active (dominant positive) without ligand binding (1), mediated by AF-1 in the N-terminal domain, in transiently transfected cells (2) and yeast (3), being related to tamoxifen-resistant growth of breast cancer (MCF-7) cells (4). The ratio of ERaE5SV to wild ERa mRNA expression significantly increased in four out of eight metastatic lesions of uterine endometrial cancers (Figure 2). Relative overexpression of ERaE5SV might contribute to the secondary spreading of uterine endometrial cancers as a dominant positive behavior, regardless of estrogen dependency (5).
Estrogen receptor beta ERb consists of 530 amino acids (Figure 3) (6) and distinctly expresses in epithelial cells of the prostate, granulose cells of the ovary (7), and osteoblastic cells of the bone (8). As ERb does not compensate for the defects that are observed in the ERa knockout mouse and in man, ERb can play a role of co-function with ERa. Enriched positive staining of ERa is visible in the nucleus of normal uterine endometrium and primary tumor. By contrast, enriched positive staining of ERb is visible in the nucleus of metastatic lesion of uterine endometrial cancer (9). In 14 of the 20 metastasis-positive cases of uterine endometrial cancer patients, the ratio of ERb to ERa in metastatic lesions was significantly higher than in the primary tumor of the corresponding cases, whereas there was no significant difference between the ratios in the other 6 cases in the metastatic lesions and primary tumors (Figure 4). The prognosis of 14 patients with high ratio in metastatic lesions was extremely poor, whereas the 36-month survival rate of the other 6 patients with low ratio in the metastatic
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Figure 1 Estrogen receptor alpha exon 5 splicing variant (ERaE5SV).
Progesterone receptor-A PR-A lacks N-terminal 164 amino acid of wild-type PR, PRB (Figure 5) (10–14). PR-A and PR-B are present in equal amounts in normal female genital tract (15). PR-A acts as a progestin-dependent, trans-dominant repressor of PR-B and other steroid receptor functions (16, 17), especially human ER transcriptional activity (18). There is no case with PR-A dominant expression. Alternation from equal expression of PR-B/PR-A to PR-B dominant expression in the metastatic lesions occurred in 3 out of 8 cases (Figure 6). Therefore, transcription of PR-A expression might be damaged, which might lead to uncontrolled overexpression of PR-B in metastatic lesions, and the PR-B could reveal a highly malignant phenotype (19). Therefore, the expression manner of ERa5SV/wild-type ERa, ERb/ERa and PR-B/PR-A might be related to metastatic potential in uterine endometrial cancers. Figure 2 Expression manner of ERaE5SV/ERa wild-type (WT) mRNA in primary tumor and the corresponding metastatic lesion of uterine endometrial cancers.
lesions was 83% (Figure 4). Therefore, the intact synchronized expression of ERb interacting ERa might be disrupted in some primary tumor and most metastatic lesions of uterine endometrial cancers, leading to poor patient prognosis (9).
Figure 3 Estrogen receptor beta (ERb).
Estrogen-related receptor alpha (Figure 7) Although estrogens are not ligands for estrogen-related receptor (ERR), one type of orphan receptor ERR can interact with ERs in competition to use the common cofactors for transcription (20–25). ERa and ERb expressions decreased with tumor progression, involving dedifferentiation
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Figure 4 Expression manner of ERb and ERa mRNAs in uterine endometrial cancers, especially in metastatic lesion, and patient prognosis.
Figure 6 Expression manner of PR-B/PR-A mRNA in primary tumor and the corresponding metastatic lesion of uterine endometrial cancers.
Figure 5 Progesterone receptor-A (PR-A, N-terminus deletion mutant).
and myometrial invasion. This could lead to the loss of estrogen dependency in growth by decreasing ERs with tumor advancement in uterine endometrial cancers. By contrast, ERR alpha (ERRa) was increased with tumor progression involving myometrial invasion, regardless of dedifferentiation (Figure 8). ERR can bind to steroid receptor coactivator family without any ligands and drive transcription activity of the target genes. Therefore, the potential of advancement might be related to increased ERRa expression with the loss of estrogen dependency in advancement (26).
ticular, the overexpression and amplification of SRC-3 are firstly reported in breast cancers (28). SRC-3 was increased with tumor progression involving myometrial invasion and dedifferentiation. The prognosis of patients with higher expression of SRC-3 in uterine endometrial cancers was extremely poor (36%), whereas the 24-month survival rate of patients with lower SRC-3 was 96% (Figure 10). There-
Steroid receptor coactivator-3 Among cofactors, the steroid receptor coactivator (SRC) family, which includes SRC-1/NCoA1, SRC-2/TIF2/GRIP1 and SRC-3/AIB1/ACTR/RAC3/TRAM-1/pCIP, are essential for transcription of steroid receptors (27) (Figure 9). In par-
Figure 7 Estrogen related receptor (ERR).
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Figure 8 Expression manner of ERRa, ERa and ERb mRNAs in uterine endometrial cancers. *p-0.001; **p-0.05.
fore, SRC-3 might contribute to tumor progression and can be used as a treatment target of the advanced uterine endometrial cancers (29).
Estrogen responsive oncogenes, c-jun and c-Ha-ras c-jun and c-Ha-ras expressions were induced by estradiol in uterine endometrial fibroblasts and cancer cells. Estrogen induced c-jun and c-Ha-ras expressions were suppressed by progestin as an antiestrogen in uterine endometrial fibroblasts, but not in uterine endometrial cancer cells (Figure 11). Therefore, the estrogen responsive oncogenes, c-jun and c-Ha-ras, are considered to be an instinct phenotype as such cancers (30, 31).
Metastasis-related genes In the metastatic process, suppression of E-cadherin and catenins leads to release of cancer cells from cancer tissue, suppression of PAI-1 leads to invasion of cancer cells, and induction of VEGF leads to angiogenesis, resulting in induction of metastasis. E-cadherin and catenin expressions were suppressed by estradiol (32), PAI-1 expression was not significantly modified by estradiol (33), and VEGF expression was induced by estradiol in well-differentiated uterine endometrial cancer cells (Figure 12) (34). Estrogen suppressed E-cadherin and catenin expressions were approximately 50% recovered by progestin (32), estrogen primed PAI-1 expression was extremely induced by progestin (33), and estrogen induced VEGF expression was approximately 50% suppressed by progestin in well-differentiated uterine endometrial cancer cells (Figure 12) (34). Therefore, estrogen
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Figure 9 Steroid receptor coactivator-3 (SRC-3).
Figure 10 Expression manner of SRC-3 mRNA in uterine endometrial cancers and patient prognosis. *p-0.05.
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Figure 11 Effect of sex steroids on estrogen responsive oncogenes, c-jun and c-Ha-ras, mRNA expressions in normal uterine endometrial fibroblasts and well-differentiated uterine endometrial cancer cells.
might induce metastatic potential and estrogen-induced potential can be partially suppressed by progestin in welldifferentiated uterine endometrial cancer cells, leading to the metastatic potential of estrogen-dependent uterine endometrial cancers being partially controlled by the administration of progestin.
Figure 12 Effect of sex steroids on metastasis-related gene expressions in well-differentiated uterine endometrial cancer cells.
Angiogenic mediators In addition, angiogenesis is essential to tumor advancement, and angiogenesis and the angiogenic mediator in gynecological cancers have been studied. In gynecological cancers, cancer of the uterine cervix, the uterine endometrium and the ovary, the main angiogenic factors include VEGF (35–39), thymidine phosphorylase (TP, platelet-derived endothelial growth factor) (40–47), cyclooxygenase (COX)-2 (48–50), interleukin (IL)-8 (51, 52), basic fibroblast growth factor (bFGF) (53–55), protease activated receptor-2 (56–58), inhibitor of DNA-binding-1 (59, 60), and the linked angiogenic transcription factors include ETS-1 (61–66) and HIF-1 (67, 68) and a main endogenous angiogenic inhibitor is interferon-gamma-inducible protein-10 (69, 70). The expression of sex steroid inducible angiogenic factors, VEGF (34, 37) with COX-2 (49) and TP (43–46) were decreased with the loss of estrogen dependency in uterine endometrial cancers. By contrast, IL-8 and bFGF expressions are sex steroid independent and increased with tumor progression (Figure 13). If the tumor conserves estrogen dependency,
Figure 13 Angiogenic factors in uterine endometrial cancers.
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medroxyprogesterone acetate, VEGF antibody, VEGF tyrosine kinase inhibitor and COX-2 inhibitor can be used. By contrast, if the tumor loses estrogen dependency with advancement, O-(chloroacetyl-carbamoyl) fumagillol (TNP470) and conventional chemotherapy can be used. In conclusion, sex steroids related phenomena are very impressive in the advancement of uterine endometrial cancers.
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Short Review
Sex steroids in uterine endometrial cancers
Jiro Fujimoto* and Eriko Sato Department of Obstetrics and Gynecology, Graduate School of Medicine, Gifu University School of Medicine, Gifu, Japan
Abstract Some uterine endometrial cancers conserve estrogen dependency in advancement. However, the concept of advancement in tumor is complicated, because it involves simple growth in primary tumor and secondary spreading. The expression manner of estrogen receptor alpha exon 5 splicing variant, ER beta, progesterone receptor-A (N-terminus deletion mutant) is associated with metastatic potential in uterine endometrial cancers. Increased estrogen-related receptor alpha expression is related to tumor advancement with the loss of estrogen dependency. Steroid receptor coactivator-3 contributes to tumor progression and can be used as a treatment target for advanced uterine endometrial cancers. Estrogen responsive oncogenes, c-jun and c-Ha-ras, are not modified by progestin in uterine endometrial cancer cells and are considered to be an instinct phenotype as such cancers. By contrast, metastatic potential of estrogen-dependent uterine endometrial cancers can be partially controlled by progestin via metastasis-related genes, E-cadherin/catenins, plasminogen activator inhibitor-1, vascular endothelial growth factor. Thus, sex steroids related phenomena are impressive in the advancement of uterine endometrial cancers. Keywords: c-Ha-ras; c-jun; E-cadherin/catenins; ER beta (ERb); estrogen receptor alpha exon 5 splicing variant (ERaE5SV); estrogen-related receptor alpha (ERRa); plasminogen activator inhibitor (PAI)-1; progesterone receptor (PR)-A; steroid receptor coactivator (SRC)-3; uterine endometrial cancer; vascular endothelial growth factor (VEGF).
Introduction Some uterine endometrial cancers conserve estrogen dependency in advancement. Tumor advancement is not simple and involves simple growth in primary tumor and secondary *Corresponding author: Jiro Fujimoto, MD, PhD, Professor, Department of Obstetrics and Gynecology, Graduate School of Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan Phone: q81-58-230-6349, Fax: q81-58-230-6348, E-mail: [email protected] Received September 22, 2010; accepted September 24, 2010; previously published online March 4, 2011
spreading metastasis with angiogenesis. To understand molecular mechanisms of tumor advancement, the expression manner of estrogen receptor alpha exon 5 splicing variant (ERaE5SV), ER beta (ERb), progesterone receptor (PR)-A, estrogen-related receptor alpha (ERRa) with steroid receptor coactivator (SRC)-3, estrogen responsive genes (oncogenes), c-jun and c-Ha-ras, metastasis-related genes, E-cadherin/catenins and plasminogen activator inhibitor (PAI)-1, and estrogen responsive angiogenic factors, vascular endothelial growth factor (VEGF), was studied.
Estrogen receptor alpha exon 5 splicing variant Among exon splicing variants, only ERaE5SV (Figure 1) is transcriptionally active (dominant positive) without ligand binding (1), mediated by AF-1 in the N-terminal domain, in transiently transfected cells (2) and yeast (3), being related to tamoxifen-resistant growth of breast cancer (MCF-7) cells (4). The ratio of ERaE5SV to wild ERa mRNA expression significantly increased in four out of eight metastatic lesions of uterine endometrial cancers (Figure 2). Relative overexpression of ERaE5SV might contribute to the secondary spreading of uterine endometrial cancers as a dominant positive behavior, regardless of estrogen dependency (5).
Estrogen receptor beta ERb consists of 530 amino acids (Figure 3) (6) and distinctly expresses in epithelial cells of the prostate, granulose cells of the ovary (7), and osteoblastic cells of the bone (8). As ERb does not compensate for the defects that are observed in the ERa knockout mouse and in man, ERb can play a role of co-function with ERa. Enriched positive staining of ERa is visible in the nucleus of normal uterine endometrium and primary tumor. By contrast, enriched positive staining of ERb is visible in the nucleus of metastatic lesion of uterine endometrial cancer (9). In 14 of the 20 metastasis-positive cases of uterine endometrial cancer patients, the ratio of ERb to ERa in metastatic lesions was significantly higher than in the primary tumor of the corresponding cases, whereas there was no significant difference between the ratios in the other 6 cases in the metastatic lesions and primary tumors (Figure 4). The prognosis of 14 patients with high ratio in metastatic lesions was extremely poor, whereas the 36-month survival rate of the other 6 patients with low ratio in the metastatic
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Figure 1 Estrogen receptor alpha exon 5 splicing variant (ERaE5SV).
Progesterone receptor-A PR-A lacks N-terminal 164 amino acid of wild-type PR, PRB (Figure 5) (10–14). PR-A and PR-B are present in equal amounts in normal female genital tract (15). PR-A acts as a progestin-dependent, trans-dominant repressor of PR-B and other steroid receptor functions (16, 17), especially human ER transcriptional activity (18). There is no case with PR-A dominant expression. Alternation from equal expression of PR-B/PR-A to PR-B dominant expression in the metastatic lesions occurred in 3 out of 8 cases (Figure 6). Therefore, transcription of PR-A expression might be damaged, which might lead to uncontrolled overexpression of PR-B in metastatic lesions, and the PR-B could reveal a highly malignant phenotype (19). Therefore, the expression manner of ERa5SV/wild-type ERa, ERb/ERa and PR-B/PR-A might be related to metastatic potential in uterine endometrial cancers. Figure 2 Expression manner of ERaE5SV/ERa wild-type (WT) mRNA in primary tumor and the corresponding metastatic lesion of uterine endometrial cancers.
lesions was 83% (Figure 4). Therefore, the intact synchronized expression of ERb interacting ERa might be disrupted in some primary tumor and most metastatic lesions of uterine endometrial cancers, leading to poor patient prognosis (9).
Figure 3 Estrogen receptor beta (ERb).
Estrogen-related receptor alpha (Figure 7) Although estrogens are not ligands for estrogen-related receptor (ERR), one type of orphan receptor ERR can interact with ERs in competition to use the common cofactors for transcription (20–25). ERa and ERb expressions decreased with tumor progression, involving dedifferentiation
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Figure 4 Expression manner of ERb and ERa mRNAs in uterine endometrial cancers, especially in metastatic lesion, and patient prognosis.
Figure 6 Expression manner of PR-B/PR-A mRNA in primary tumor and the corresponding metastatic lesion of uterine endometrial cancers.
Figure 5 Progesterone receptor-A (PR-A, N-terminus deletion mutant).
and myometrial invasion. This could lead to the loss of estrogen dependency in growth by decreasing ERs with tumor advancement in uterine endometrial cancers. By contrast, ERR alpha (ERRa) was increased with tumor progression involving myometrial invasion, regardless of dedifferentiation (Figure 8). ERR can bind to steroid receptor coactivator family without any ligands and drive transcription activity of the target genes. Therefore, the potential of advancement might be related to increased ERRa expression with the loss of estrogen dependency in advancement (26).
ticular, the overexpression and amplification of SRC-3 are firstly reported in breast cancers (28). SRC-3 was increased with tumor progression involving myometrial invasion and dedifferentiation. The prognosis of patients with higher expression of SRC-3 in uterine endometrial cancers was extremely poor (36%), whereas the 24-month survival rate of patients with lower SRC-3 was 96% (Figure 10). There-
Steroid receptor coactivator-3 Among cofactors, the steroid receptor coactivator (SRC) family, which includes SRC-1/NCoA1, SRC-2/TIF2/GRIP1 and SRC-3/AIB1/ACTR/RAC3/TRAM-1/pCIP, are essential for transcription of steroid receptors (27) (Figure 9). In par-
Figure 7 Estrogen related receptor (ERR).
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Figure 8 Expression manner of ERRa, ERa and ERb mRNAs in uterine endometrial cancers. *p-0.001; **p-0.05.
fore, SRC-3 might contribute to tumor progression and can be used as a treatment target of the advanced uterine endometrial cancers (29).
Estrogen responsive oncogenes, c-jun and c-Ha-ras c-jun and c-Ha-ras expressions were induced by estradiol in uterine endometrial fibroblasts and cancer cells. Estrogen induced c-jun and c-Ha-ras expressions were suppressed by progestin as an antiestrogen in uterine endometrial fibroblasts, but not in uterine endometrial cancer cells (Figure 11). Therefore, the estrogen responsive oncogenes, c-jun and c-Ha-ras, are considered to be an instinct phenotype as such cancers (30, 31).
Metastasis-related genes In the metastatic process, suppression of E-cadherin and catenins leads to release of cancer cells from cancer tissue, suppression of PAI-1 leads to invasion of cancer cells, and induction of VEGF leads to angiogenesis, resulting in induction of metastasis. E-cadherin and catenin expressions were suppressed by estradiol (32), PAI-1 expression was not significantly modified by estradiol (33), and VEGF expression was induced by estradiol in well-differentiated uterine endometrial cancer cells (Figure 12) (34). Estrogen suppressed E-cadherin and catenin expressions were approximately 50% recovered by progestin (32), estrogen primed PAI-1 expression was extremely induced by progestin (33), and estrogen induced VEGF expression was approximately 50% suppressed by progestin in well-differentiated uterine endometrial cancer cells (Figure 12) (34). Therefore, estrogen
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Figure 9 Steroid receptor coactivator-3 (SRC-3).
Figure 10 Expression manner of SRC-3 mRNA in uterine endometrial cancers and patient prognosis. *p-0.05.
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Figure 11 Effect of sex steroids on estrogen responsive oncogenes, c-jun and c-Ha-ras, mRNA expressions in normal uterine endometrial fibroblasts and well-differentiated uterine endometrial cancer cells.
might induce metastatic potential and estrogen-induced potential can be partially suppressed by progestin in welldifferentiated uterine endometrial cancer cells, leading to the metastatic potential of estrogen-dependent uterine endometrial cancers being partially controlled by the administration of progestin.
Figure 12 Effect of sex steroids on metastasis-related gene expressions in well-differentiated uterine endometrial cancer cells.
Angiogenic mediators In addition, angiogenesis is essential to tumor advancement, and angiogenesis and the angiogenic mediator in gynecological cancers have been studied. In gynecological cancers, cancer of the uterine cervix, the uterine endometrium and the ovary, the main angiogenic factors include VEGF (35–39), thymidine phosphorylase (TP, platelet-derived endothelial growth factor) (40–47), cyclooxygenase (COX)-2 (48–50), interleukin (IL)-8 (51, 52), basic fibroblast growth factor (bFGF) (53–55), protease activated receptor-2 (56–58), inhibitor of DNA-binding-1 (59, 60), and the linked angiogenic transcription factors include ETS-1 (61–66) and HIF-1 (67, 68) and a main endogenous angiogenic inhibitor is interferon-gamma-inducible protein-10 (69, 70). The expression of sex steroid inducible angiogenic factors, VEGF (34, 37) with COX-2 (49) and TP (43–46) were decreased with the loss of estrogen dependency in uterine endometrial cancers. By contrast, IL-8 and bFGF expressions are sex steroid independent and increased with tumor progression (Figure 13). If the tumor conserves estrogen dependency,
Figure 13 Angiogenic factors in uterine endometrial cancers.
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medroxyprogesterone acetate, VEGF antibody, VEGF tyrosine kinase inhibitor and COX-2 inhibitor can be used. By contrast, if the tumor loses estrogen dependency with advancement, O-(chloroacetyl-carbamoyl) fumagillol (TNP470) and conventional chemotherapy can be used. In conclusion, sex steroids related phenomena are very impressive in the advancement of uterine endometrial cancers.
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