Expression of ERβ and Its Co-Regulators p300 and NCoR in Human Transitional Cell Bladder Cancer

Kontos, Stylianos; Papatsoris, Athanasios; Kominea, Athina; Melachrinou, Maria; Tanoglidi, Anna; Kachrilas, Stefanos; Karavitakis, Markos; Balampani, Eleni; Sotiropoulou-Bonikou, Georgia

doi:10.1159/000324262

Cited by 11 publications

(7 citation statements)

References 55 publications

(30 reference statements)

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“…Thirdly, the role of the synergistic inhibition of NBS-1 activation by HCPT and genistein in the malformation of the MRN complex requires further exploration. In the end, genistein is a well-known botanic estrogen, and estrogen has been shown to be expressed in bladder transitional cell cancer, and it was negatively correlated with tumor grade [34]. Whether the estrogen effect of genistein is correlated with the synergistic growth inhibitory effect remain to be explored in the future.…”

Section: Discussionmentioning

confidence: 99%

Genistein Sensitizes Bladder Cancer Cells to HCPT Treatment In Vitro and In Vivo via ATM/NF-κB/IKK Pathway-Induced Apoptosis

Wang

Zhang

et al. 2013

PLoS ONE

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Bladder cancer is the most common malignant urological disease in China. Hydroxycamptothecin (HCPT) is a DNA topoisomerase I inhibitor, which has been utilized in chemotherapy for bladder cancer for nearly 40 years. Previous research has demonstrated that the isoflavone, genistein, can sensitize multiple cancer cell lines to HCPT treatment, such as prostate and cervical cancer. In this study, we investigated whether genistein could sensitize bladder cancer cell lines and bladder epithelial cell BDEC cells to HCPT treatment, and investigated the possible underlying molecular mechanisms. Genistein could significantly and dose-dependently sensitize multiple bladder cancer cell lines and BDEC cells to HCPT-induced apoptosis both in vitro and in vivo. Genistein and HCPT synergistically inhibited bladder cell growth and proliferation, and induced G2/M phase cell cycle arrest and apoptosis in TCCSUP bladder cancer cell and BDEC cell. Pretreatment with genistein sensitized BDEC and bladder cancer cell lines to HCPT-induced DNA damage by the synergistic activation of ataxia telangiectasia mutated (ATM) kinase. Genistein significantly attenuated the ability of HCPT to induce activation of the anti-apoptotic NF-κB pathway both in vitro and in vivo in a bladder cancer xenograft model, and thus counteracted the anti-apoptotic effect of the NF-κB pathway. This study indicates that genistein could act as a promising non-toxic agent to improve efficacy of HCPT bladder cancer chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Genistein Sensitizes Bladder Cancer Cells to HCPT Treatment In Vitro and In Vivo via ATM/NF-κB/IKK Pathway-Induced Apoptosis

Wang

Zhang

et al. 2013

PLoS ONE

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“…An important role for estrogen signaling is becoming apparent in UCB (20–24). ERβ protein is the predominant ER in bladder, expressed in up to 77% of clinical UCB, whereas ERα expression is infrequent (<5%) (22,25,26).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the relationship between ERβ and tumor stage or patient outcomes is disputed (22,25,26), and the relationship of ERβ to histological cancer features such as perineural invasion, concomitant carcinoma in situ or LVI has not yet been described. While selective estrogen receptor modulators (SERM) have been shown to inhibit the proliferation of some UCB cell lines and murine xenografts, which ER isoform(s) is being targeted has not been addressed (20–24). Research in preclinical models has generally not interrogated the ERβ isoform specifically, with most studies evaluating a non-specific ERα/ERβ agonist in UCB cell lines expressing both ERα and ERβ.…”

Section: Introductionmentioning

confidence: 99%

Estrogen receptor-β expression and pharmacological targeting in bladder cancer

et al. 2013

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A role for estrogen signaling in urothelial carcinoma of the bladder (UCB) is suggested to be associated with more advanced disease with worse outcomes in women. Estrogen receptor β (ERβ) is the predominant receptor in bladder tissues. We aimed to ascertain whether ERβ correlates with clinicopathological predictors of aggressive bladder cancer and worse survival outcomes. ERβ was measured by immunohistochemistry in malignant and adjacent benign bladder tissues in patients (N=72) with UCB who underwent radical cystectomy. ERβ expression was tested for statistical association with clinicopathological variables and patient survival. ERβ expression was determined in bladder cancer cell lines, and the effects of the selective estrogen modulator tamoxifen and the ERβ agonist diarylpropionitrile on cell growth were determined. The ERβ level was significantly higher in malignant vs. benign urothelium (P<0.001) and was strongly associated with aggressive tumor histology characterized by lymphovascular (P=0.008) and perineural (P=0.006) invasion, and clinical histories of pelvic irradiation (P=0.005), hydronephrosis (P=0.022) and no intravesical chemotherapy (P=0.038). All patients with a high (>70%) percentage of ERβ positivity in tissue with >3-month follow-up developed recurrent disease (P=0.009). Higher ERβ level was predictive of worse recurrence-free and overall survival following cystectomy, after adjustment for tumor stage, and remained significantly associated with recurrence-free survival in the multivariable analysis including tumor stage, nodal stage and lymphovascular invasion. Activation of ERβ in bladder cancer cell lines led to significant increases in proliferation, while pharmacological inhibition with tamoxifen blocked cell growth. Our study supports a role for ERβ in aggressive UCB. Pharmacological targeting of ERβ warrants further investigation as a therapeutic strategy in UCB.

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“…A recent report indicated weak expression of ERα in 27% of primary bladder cancer tissues, with no correlation between ERα and tumor recurrence, progression, or cancer-specific survival [20]. In contrast, strong ERβ is detected in human bladder cancers in multiple studies, with up to 81% of tumors expressing this form of ER [8,9,20,22,35,39,40]. Expression of ERβ appears to be greater in high-grade versus low-grade tumors [20,35] and is associated with recurrence and progression of low-grade tumors, recurrence of muscle-invasive tumors, and reduced cancer-specific survival [20].…”

Section: Introductionmentioning

confidence: 99%

Chemoprevention of BBN-Induced Bladder Carcinogenesis by the Selective Estrogen Receptor Modulator Tamoxifen

George¹,

Tovar-Sepulveda²,

Shen³

et al. 2011

CLINICAL/TRANSLATIONAL - Endocrine Neoplasia

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Bladder cancer is the fifth most frequent tumor in men and ninth in women in the United States. Due to a high likelihood of recurrence, effective chemoprevention is a significant unmet need. Estrogen receptors (ERs), primarily ERβ, are expressed in normal urothelium and urothelial carcinoma, and blocking ER function with selective ER modulators such as tamoxifen inhibits bladder cancer cell proliferation in vitro. Herein, the chemoprotective potential of tamoxifen was evaluated in female mice exposed to the bladder-specific carcinogen, N -butyl-N -(4-hydroxybutyl) nitrosamine (BBN). Carcinogen treatment resulted in a 76% tumor incidence and increased mean bladder weights in comparison to controls. In contrast, mice receiving tamoxifen concurrent (8-20 weeks) or concurrent and subsequent (8-32 weeks) to BBN administration had no change in bladder weight and only 10% to 14% incidence of tumors. Non-muscle-invasive disease was present in animals treated with tamoxifen before (5-8 weeks) or after (20-32 weeks) BBN exposure, while incidence of muscle-invasive bladder carcinoma was reduced. ERβ was present in all mice and thus is a potential mediator of the tamoxifen chemoprotective effect. Surprisingly, ERα expression, which was detected in 74% of the mice exposed to BBN alone but not in any control mice, was correlated with tumor incidence, indicating a possible role for this receptor in carcinogen-induced urothelial tumorigenesis. Thus, these data argue that both ERα and ERβ play a role in modulating carcinogen-induced bladder tumorigenesis. Administration of tamoxifen should be tested as a chemopreventive strategy for patients at high risk for bladder cancer recurrence.Translational Oncology (2013) 6, 244-255 IntroductionAs the fifth most common cancer in men and ninth most common in women in the United States, urinary bladder cancer accounts for significant morbidity and mortality. There are estimated to be more than 73,000 new bladder cancer cases in 2012 [1] with urothelial carcinoma accounting for approximately 90% of these; the remainder is composed of squamous cell carcinomas, adenocarcinomas, and other rare histologies [2]. Approximately 70% of all new bladder cancer cases are classified as non-muscle-invasive (Ta, T1, Tis), while the remaining 30% are muscle-invasive (T2-T4) and generally lead to cystectomy. Bladder cancer recurs at a very high rate of 50% to 90% depending on the tumor stage, grade, and number of primary tumors, and this necessitates lifetime monitoring for tumor recur-

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Expression of ERβ and Its Co-Regulators p300 and NCoR in Human Transitional Cell Bladder Cancer

Cited by 11 publications

References 55 publications

Genistein Sensitizes Bladder Cancer Cells to HCPT Treatment In Vitro and In Vivo via ATM/NF-κB/IKK Pathway-Induced Apoptosis

Genistein Sensitizes Bladder Cancer Cells to HCPT Treatment In Vitro and In Vivo via ATM/NF-κB/IKK Pathway-Induced Apoptosis

Estrogen receptor-β expression and pharmacological targeting in bladder cancer

Chemoprevention of BBN-Induced Bladder Carcinogenesis by the Selective Estrogen Receptor Modulator Tamoxifen

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