• Biomolecules & Therapeutics
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• 제20권3호
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• pp.256-267
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• 2012

Tamoxifen is a central component of the treatment of estrogen receptor (ER)-positive breast cancer as a partial agonist of ER. It has been clinically used for the last 30 years and is currently available as a chemopreventive agent in women with high risk for breast cancer. The most challenging issue with tamoxifen use is the development of resistance in an initially responsive breast tumor. This review summarizes the roles of ER as the therapeutic target of tamoxifen in cancer treatment, clinical values and issues of tamoxifen use, and molecular mechanisms of tamoxifen resistance. Emerging knowledge on the molecular mechanisms of tamoxifen resistance will provide insight into the design of regimens to overcome tamoxifen resistance and discovery of novel therapeutic agents with a decreased chance of developing resistance as well as establishing more efficient treatment strategies.

• Toxicological Research
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• 제27권2호
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• pp.85-93
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• 2011

Selective estrogen receptor modulators (SERMs) are synthetic molecules which bind to estrogen receptors (ER) and can modulate its transcriptional capabilities in different ways in diverse estrogen target tissues. Tamoxifen, the prototypical SERM, is extensively used for targeted therapy of ER positive breast cancers. Unfortunately, the use of tamoxifen is associated with acquired resistance and some undesirable side effects. This study investigated the availability of the conventional SERMs on the TAM-resistance breast cancer cells. SERMs showed more effectiveness in MCF-7 cells than tamoxifen resistant cells, except toremifene and ospemifene. Especially, toremifene was more efficacious in tamoxifen resistant cells than MCF-7. Ospemifene had similar cytotoxic activity on the two types of breast cancers. The other SERMs used in this experiment didn't inhibit efficiently the proliferation of tamoxifen resistant cells. These results support the possibility to usage of toremifene on tamoxifen resistant cancer. The effectiveness by toremifene on tamoxifen resistant cells might be different pathways from the apoptosis and the autophagy. Further study should be needed to elucidate the underlying mechanism of effect of toremifene on tamoxifen resistant cancer.

• BMB Reports
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• 제29권4호
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• pp.314-320
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• 1996

The effects of non-cytotoxic concentrations of tamoxifen, verapamil, and trifluoperazine on doxorubicin cytotoxicity in five human breast cancer cell lines were studied. A non-cytotoxic concentration of tamoxifen resulted in enhanced doxorubicin cytotoxicity in HTB-123, HTB-26, and MCF-7. In these three cell lines, a combination of tamoxifen with verapamil resulted in even more increased doxorubicin cytotoxicity. Addition of verapamil or trifluoperazine alone did not influence the doxorubicin cytotoxicity significantly. Only in HTB-19 did coincubation with verapamil increase the doxorubicin cytotoxicity. In HTB-123, combination of tamoxifen with trifluoperazine increased the doxorubicin cytotoxicity significantly. In the cell lines where co-incubation with tamoxifen increased doxorubicin sensitivity, high estrogen receptor expression was detected. However, HTB-20, where tamoxifen did not enhance doxorubicin action, was also estrogen receptor positive. None of the cell lines had multidrug resistance related drug efflux and drug retention was not increased by the treatment with tamoxifen and verapamil. Cell cycle traverses were not altered by incubation with tamoxifen, verapamil or combinations thereof. These observatlons suggest mechanism of non-cytotoxic concentrations of tamoxifen and verapamil on doxorubicin cytotoxicity may involve one or more other cellular processes besides those of interference of estrogen binding to its receptor, cell cycle perturbation, or drug efflux blocking.

• Asian Pacific Journal of Cancer Prevention
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• 제13권12호
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• pp.6101-6104
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• 2012

Background: Breast cancer accounts about one million from total annual ten million new diagnosed cases of neoplasia worldwide and is the main cause of death due to cancer in women. Tamoxifen is the most popular selective estrogen receptor modulator used in anti estrogen treatments. Tamoxifen must be converted into its metabolite endoxifen for biologic effects; this conversion process is catalysed by highly polymorphic cytochrome P450 2D6 (CYP2D6). This study surveyed copy number variation of the CYP2D6 gene and its possible correlation with Tamoxifen resistance in breast cancer patients. Methods: This case control study was performed on samples taken from 79 patients with breast cancer who used tamoxifen in Yazd and Tehran Cities, Iran. Real time reactions were conducted for 10 healthy samples using the comparative $C_t$ (Cycles threshold) method, each pair of genes being compared and samples with ratios around 1 were taken as control samples. Proliferation reactions were done by Real-Time PCR ABI Prism 7500. All registered data were transformed into SPSS 15 program and analyzed. Results: Efficiency of PCR for both CYP2D6 and ALB genes was 100%. From all 23 drug resistant patients 21.7% had one copy, 47.8% two copies and 30.4% had three copies. Also from all 56 drug sensitive patients, 26.8% had one copy, 51.8% two copies and 21.4% had three copies. The percentage of patients with one and two copies was similar between two groups but patients with three copies were more likely to belong to the drug resistant group more. Odd ratios for one and two copies were 0.759 and 0.853 respectively, indicating possible protective effects while that for three copies was 1.604. Conclusions: Based on our study there is no significant link between CYP2D6 gene copy numbers and tamoxifen resistance in women with breast cancer. But more studies considering other influencing factors appear warranted.

• BMB Reports
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• 제50권12호
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• pp.615-620
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• 2017

Fibronectin (FN) plays important roles in the EMT in a variety of cancer cell types. However, the mechanism by which FN expression is regulated in tamoxifen-resistant (TamR) breast cancer cells has not yet been fully elucidated. Aberrant FN expression was associated with poor prognosis in patients with luminal type A breast cancer. In addition, FN was upregulated in TamR cells. To investigate the mechanism by which FN expression is regulated, we assessed the levels of phosphorylated Akt, JNK, and STAT3 and found that they were all increased in TamR cells. Induction of FN expression was dampened by LY294002 or AKT IV in TamR cells. Furthermore, FN expression was increased by constitutively active (CA)-Akt overexpression in tamoxifen-sensitive MCF7 (TamS) cells and colony formation of TamR cells was blocked by AKT IV treatment. Taken together, these results demonstrate that FN expression is upregulated through the PI-3K/Akt pathway in tamoxifen-resistant breast cancer cells.

• BMB Reports
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• 제51권9호
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• pp.450-455
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• 2018

Tamoxifen (TAM) is commonly used to treat estrogen receptor (ER)-positive breast cancer. Despite the remarkable benefits, resistance to TAM presents a serious therapeutic challenge. Since several HOX transcription factors have been proposed as strong candidates in the development of resistance to TAM therapy in breast cancer, we generated an in vitro model of acquired TAM resistance using ER-positive MCF7 breast cancer cells (MCF7-TAMR), and analyzed the expression pattern and epigenetic states of HOX genes. HOXB cluster genes were uniquely up-regulated in MCF7-TAMR cells. Survival analysis of in slico data showed the correlation of high expression of HOXB genes with poor response to TAM in ER-positive breast cancer patients treated with TAM. Gain- and loss-of-function experiments showed that the overexpression of multi HOXB genes in MCF7 renders cancer cells more resistant to TAM, whereas the knockdown restores TAM sensitivity. Furthermore, activation of HOXB genes in MCF7-TAMR was associated with histone modifications, particularly the gain of H3K9ac. These findings imply that the activation of HOXB genes mediate the development of TAM resistance, and represent a target for development of new strategies to prevent or reverse TAM resistance.

• Archives of Pharmacal Research
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• 제19권5호
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• pp.342-347
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• 1996

Doxorubicin, one of the clinically most useful anticancer agents, is used alone or in combination with other drugs against a wide variety of tumors, recently. But cancer cells developed resistance to this agent in many ways. This resistance is an important limiting factor of doxorubicin for anticancer drug. We newly established doxorubicin-resistant HCT15/CL02 subline from parental HCT15 human adenocarcinoma colon cancer cells. HCT15/CL02 revealed resistance to doxorubicin about 85-fold of its parental cells, and it also revealed cross-resistance to actinomycin D, etoposide and vinblastine but not to displatin and tamoxifen. And verapamil, a reversal agent of multidrug-resistance (MDR) by P-glycoprotein, elevated the cytotoxicity of doxorubicin against both HCT15 and GCT15/CL02 cells. But the relative resistant rate was not reduced. Verapamil had no effects on the tosicity of cisplatin to the both cell lines. These results indicate that HCT15/CL02 cells have some functionally complex mechanisms for MDR.

• 생명과학회지
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• 제26권12호
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• pp.1383-1391
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• 2016

타목시펜과 같은 항에스트로젠은 ER 양성의 초기 유방암 환자에게 사용되고 있다. 그러나 대부분의 환자에서 이 항에스트로젠에 대한 내성 발현은 불가피하게 발생한다. BCAR3 유전자는 사람의 에스트로젠 의존성 유방암에서 tamoxifen 내성유도를 야기하는 단백질로 발견되었다. 우리들은 이전에 이 BCAR3 유전자가 세포주기 진행과 EGF와 인슐린에 의한 DNA 합성 신호전달경로를 조절한다고 보고하였다. 본 연구에서는, 비종양성 정상적인 인간유방상피세포인 MCF-12A세포에서 c-Jun 전자의 조절에 대한 BCAR3유전자의 기능적인 역할을 조사하였다. BCAR3의 일시적인 발현 또는 지속적인 발현이 c-Jun mRNA와 단백질의 발현을 증가하는 것을 발견하였다. 또한 BCAR3 발현 유전자의 미세주사에 의해 세포 증식이 증가하였다. 이 c-Jun의 발현 증가는 promoter의 활성화를 통해 일어난다. 또한 BCAR3에 의한 c-Jun 발현 유도가 억제성 Ras, Rac, Rho에 의해 억제되었다. 다음으로 EGF 성장인자에 의한 c-Jun 발현 유도에 대한 BCAR3의 영향을 단일 세포 미세주사법에 의해 조사하였다. BCAR3 항체, BCAR3의 siRNA와 같은 BCAR3의 기능을 억제할 수 있는 물질들을 세포로 미세주사하면 EGF에 의한 c-Jun의 발현을 억제하였지만, IGF-1 성장인자에 의한 c-Jun 발현은 억제하지 않았다. 이러한 결과들로부터 BCAR3는 c-Jun 단백질 발현 유도와 세포 증식에 중요한 역할을 하며, 여기에는 Ras, Rac, Rho와 같은 GTPase들이 필요하다는 것을 발견하였다.

• 생명과학회지
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• 제32권11호
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• pp.882-889
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• 2022

Breast cancer anti-estrogen resistance 3 (BCAR3)는 유방암에서 항에스트로겐 내성을 유도하는 유전자들 중의 하나로 발견되었다. 우리는 이미 BCAR3가 c-jun, activator protein-1, serum response element의 promoter 등을 활성화하는 것을 보고하였다. 본 연구에서 우리는 정상 유방세포인 MCF-12A에서 estrogen response element (ERE) 활성에서의 BCAR3의 기능을 조사하였다. BCAR3의 발현이 ERE를 활성화하는 것을 발견하였다. 이 ERE 활성화는 17β-estradiol에 의해 더욱 증가하였고, 이는 항에스트론겐인 tamoxifen에 의해 억제되지 않았다. 다음으로 우리는 ERE 활성화를 이끄는 BCAR3의 신호전달 경로를 연구하였다. BCAR3에 의한 ERE 활성화는 phosphatidylinositol (PI) 3-kinase 경로 억제제인 LY294002와 AZD5363에 의해서는 억제되었으나, Mitogen-activated protein kinase 경로 억제제인 PD98059와 U0126에 의해서는 억제되지 않았다. ERE 활성화는 PI3-kinase의 catalytic subunit p110α와 Akt의 active mutant에 의해서는 유도되었고, 이 활성화는 추가적인 BCAR3에 의해서는 더욱 증가하지 않았다. 이러한 결과로부터 우리는 BCAR3가 PI3-kinase/Akt 신호전달경로를 통하여 ERE 활성화에 중요한 역할을 하는 것을 제시한다.

• Journal of Yeungnam Medical Science
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• 제28권2호
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• pp.153-164
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• 2011

Background: It has been reported that estrogen receptor beta ($ER{\beta}$) mRNA expression was down-regulated during carcinogenesis and was inversely related to estrogen receptor alpha ($ER{\alpha}$) expression in breast cancer. The association of $ER{\beta}$ mRNA expression to tamoxifen resistance has also been reported. In this study, the expression of $ER{\alpha}$ and $ER{\beta}$ via immunohistochemistry (IHC) and reverse transcription-polymerase chain reaction (RT-PCR) was prompted, and an attempt was made to find out the relationship between $ER{\beta}$ expression and recurrence in the hormonal therapy group, and between $ER{\beta}$ expression and known prognostic factors. Methods: Tumor specimens were obtained at surgery from 67 female breast cancer patients during the period of September 1995 to December 2000. All the specimens were frozen in liquid nitrogen and kept at $-70^{\circ}C$ until they were used. The medical records were analyzed retrospectively. The expressions of ER were analyzed using IHC and RT-PCR methods. Results: The median follow-up was at 93.0 months (range: 14-157 months). The percentage of $ER{\alpha}+/ER{\beta}+$, $ER{\alpha}+/ER{\beta}-$, $ER{\alpha}-/ER{\beta}+$, and $ER{\alpha}-/ER{\beta}$ group were 35.9% 9.4%, 47.2%, and 7.5%, respectively, in 53 patients with hormonal therapy. $ER{\beta}$ was positive in 42 (82.3%) of 51 ER-positive patients. In the hormonal therapy group, the recurrence rates of each group was 15.8%, 0%, 40.0%, and 0%, respectively. In this group, the $ER{\beta}$ expression tended to recur, but there was no clinical significance (p=0.084). Conclusion: The $ER{\beta}$ expression may be a predictive marker of a poor response to endocrine therapy in breast cancer patients, although this needs to be confirmed in additional studies.