Tamoxifen inhibits hepatoma cell growth through an estrogen receptor independent mechanism

Jiang, Shun Yuan; Shyu, Rong-Yaun; Yeh, Ming‐Yang; Jordan, V. Craig

doi:10.1016/0168-8278(95)80038-7

Cited by 36 publications

(17 citation statements)

References 31 publications

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“…Hishida et al reported that 40 out of 48 HCC clinical samples showed hypermethylation at the promoter region of ESR1 (gene name of estrogen receptor alpha), and the expression level for ESR1 transcripts was decreased more than 90% in 24 HCC samples (mostly from men) relative to normal liver (Hishida et al, 2013). Jiang et al showed that ERα protein expression was barely found in human liver cancer cell lines (Jiang et al, 1995); however, Liu et al showed that ERα proteins were expressed in most of these human liver cancer cell lines and almost all human HCC tumors (Liu et al, 2009). The latter did not mention which ERα antibody they used or which size of ERα bands they blotted (Liu et al, 2009).…”

Section: Protective Roles Of Erα In Liver Cancermentioning

confidence: 99%

Interplay of estrogen receptors and FOXA factors in the liver cancer

Zhao

2015

Molecular and Cellular Endocrinology

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Liver cancer is the fifth most common cancer in human with male dominance. Sexual dimorphism of liver cancer is conserved from rodents to humans, which was firstly found in mice in late 1930s and female mice were resistant to liver cancer. Sex hormones were found to affect the incidence of liver cancer in rodents. Estrogen receptor alpha (ERα)-mediated estrogen signaling or androgen receptor-mediated androgen signaling prevents or promotes the growth of rodent liver tumors, respectively. Forkhead box protein A (Foxa) factors, Foxa1 and Foxa2, also known as pioneer transcription factors in liver specification, are essential for both estrogen and androgen signaling by acting as central regulators of sexual dimorphism in liver cancer. This review mainly focuses on the interplay between ERα and FOXA factors in liver cancer, and summarizes recent breakthrough studies in elucidating the mechanisms of sexual dimorphism in liver cancer.

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Section: Protective Roles Of Erα In Liver Cancermentioning

confidence: 99%

Interplay of estrogen receptors and FOXA factors in the liver cancer

Zhao

2015

Molecular and Cellular Endocrinology

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“…The persistent administration of estrogens, particularly in the form of oral contraceptives, has been associated with an increased incidence of hepatic adenomas and with a slightly increased incidence of HCC [9]. The antiestrogenic compound tamoxifen has been shown to reduce the level of estrogen receptors in the liver [11]. HCC affects men more often than women with a male:female ratio of 4:1.…”

Section: Hormonal Therapymentioning

confidence: 99%

Systemic Therapy of Advanced Hepatocellular Carcinoma: How Hopeful Should We Be?

2006

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Worldwide, hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death. In the U.S., 18,510 new cancers of the liver and intrahepatic bile duct are expected in 2006, with an estimated 16,200 deaths. The incidence rates for HCC in the U.S. continued to rise steadily through 1998 and doubled during the period 1975-1995. Unresectable or metastatic HCC carries a poor prognosis, and systemic therapy with cytotoxic agents provides marginal benefit. A majority of HCC patients (>80%) presents with advanced or unresectable disease. Even for those with resected disease, the recurrence rate can be as high as 50% at 2 years. Because of the poor track record of systemic therapy in HCC, there has been a sense of nihilism for this disease in the oncology community for decades. However, with the arrival of newly developed molecularly targeted agents and the success of some of these agents in other traditionally challenging cancers, like renal cell carcinoma, there has recently been renewed interest in developing systemic therapy for HCC. This review attempts to concisely summarize the historical perspective and the current status of systemic therapy development in HCC. The Oncologist

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“…[9][10][11][12][13][14] However, TMX at higher dosages (6-8 times that used for ER-positive breast carcinoma) is known to have therapeutic actions independent of ER status, 15 and such ER-independent mechanisms for TMX have been shown in HCC. 16,17 Thus, high-dose TMX would theoretically have therapeutic actions on both ER-positive and -negative HCC. 18,19 This multicenter trial was designed to test this hypothesis and assess the possible dose-response relation of TMX with respect to survival and quality of life (QoL) in patients with inoperable HCC.…”

mentioning

confidence: 99%

High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: A multicenter randomized controlled trial

et al. 2002

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In the Asia-Pacific region and elsewhere, almost 85% of patients with hepatocellular carcinoma (HCC) are inoperable at diagnosis and have a dismal prognosis. Tamoxifen (TMX) is believed to inhibit HCC positive for estrogen receptor (ER), but most HCCs are ER negative. Results of previous phase 3 trials in inoperable HCC have been conflicting and inconclusive. At higher doses, however, TMX inhibits HCC through ER-independent mechanisms. A multicenter randomized controlled trial was performed to assess the role of high-dose TMX versus placebo (P) in the treatment of patients with inoperable HCC with respect to survival and quality of life (QoL). A total of 329 patients from 10 centers in 9 countries in the Asia-Pacific region enrolled in a double-blind randomized controlled trial of TMX 120 mg/d (TMX120) against P as a control arm with an intermediate dosage of TMX 60 mg/d (TMX60) to assess possible dose response. An independent data monitoring committee reviewed all aspects of the trial. QoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. Three-month survival rates for the P, TMX60, and TMX120 groups were 44%, 41%, and 35%, respectively, with a statistically significant trend difference in survival across the 3 treatment regimens (P ‫؍‬ .011). There was a significantly higher risk of death in the TMX120 group compared with the P group (hazard ratio, 1.39; 95% confidence interval, 1.07-1.81). Adverse drug reactions were reported in 3% (9 patients), and 8 patients were lost to follow-up. In conclusion, TMX does not prolong survival in patients with inoperable HCC and has an increasingly negative impact with increasing dose. No appreciable advantage to QoL with TMX was observed. H epatocellular carcinoma (HCC) is an important malignancy worldwide. In many parts of the Asia-Pacific region, the age-standardized mortality is in excess of 20 per 100,000. Surgery currently offers the only chance of prolonged survival, but only 10% to 15% of HCCs are operable at diagnosis. 1,2 There is currently no proven treatment modality that prolongs survival in patients with inoperable HCC. 3 Estrogen receptor (ER)-positive HCC responds to treatment with tamoxifen (TMX), 4 but more than 50% of HCCs are ER negative, including HCCs found in southeast Asia. 5-8 TMX at dosages relevant for ER-positive breast carcinoma (20-60 mg/d) was nevertheless used in a number of phase 3 trials in which the ER status of HCC was not determined. The results of these trials have been conflicting and inconclusive. [9][10][11][12][13][14] However, TMX at higher dosages (6-8 times that used for ER-positive breast carcinoma) is known to have therapeutic actions independent of ER status, 15 and such ER-independent mechanisms for TMX have been shown in HCC. 16,17 Thus, high-dose TMX would theoretically have therapeutic actions on both ER-positive and -negative HCC. 18,19 This multicenter trial was designed to test this hypothesis and

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Tamoxifen inhibits hepatoma cell growth through an estrogen receptor independent mechanism

Cited by 36 publications

References 31 publications

Interplay of estrogen receptors and FOXA factors in the liver cancer

Interplay of estrogen receptors and FOXA factors in the liver cancer

Systemic Therapy of Advanced Hepatocellular Carcinoma: How Hopeful Should We Be?

High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: A multicenter randomized controlled trial

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