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Breast cancer
Endoxifen Concentration Is Associated with Recurrence-Free Survival in Hormone-Sensitive Breast Cancer Patients
Beomki Lee, Seok Jin Nam, Seok Won Kim, Jonghan Yu, Byung-Joo Chae, Se Kyung Lee, Jai Min Ryu, Jeong Eon Lee, Soo-Youn Lee
Cancer Res Treat. 2025;57(1):140-149.   Published online June 18, 2024
DOI: https://doi.org/10.4143/crt.2023.1285
AbstractAbstract PDFPubReaderePub
Purpose
The metabolism of tamoxifen is influenced by various cytochrome p450 enzymes, including CYP2D6 and CYP2C19, leading to variations in the levels of endoxifen, even with the same tamoxifen dose. However, the clinical significance of endoxifen for the prognosis of breast cancer patients remains controversial. This study aimed to elucidate the relevance of endoxifen level to recurrence-free survival censored with tamoxifen discontinuation (RFSt), representing the RFS for tamoxifen itself, of breast cancer patients and determine a suitable cutoff for prognostication.
Materials and Methods
The study included 478 breast cancer patients. Tamoxifen and its metabolites, including endoxifen, were measured using liquid chromatography-tandem mass spectrometry. An optimal cutoff was determined with maximally selected rank statistics. Survival analysis and Cox regression were conducted based on this cutoff.
Results
An endoxifen level of 21.00 ng/mL was the optimal cutoff for prognostication. Survival analysis revealed a statistically significant difference in RFSt between the low endoxifen group (≤ 21.00 ng/mL) and the high endoxifen group (> 21.00 ng/mL) (log-rank test, p=0.032). The 10-year probability of RFSt was 83.2% (95% confidence interval [CI], 77.0 to 89.9) and 88.3% (95% CI, 83.3 to 93.5) in the low and high endoxifen groups, respectively. Multivariable Cox proportional hazards regression indicated endoxifen concentration as a significant factor associated with prognosis.
Conclusion
Endoxifen could serve as a marker for appropriate tamoxifen treatment with a cutoff of 21.00 ng/mL. Based on this cutoff, therapeutic drug monitoring would benefit patients displaying suboptimal endoxifen concentrations.
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Toremifene, an Alternative Adjuvant Endocrine Therapy, Is Better Than Tamoxifen in Breast Cancer Patients with CYP2D6*10 Mutant Genotypes
Xin Li, Zehao Li, Lin Li, Tong Liu, Cheng Qian, Yanlv Ren, Zhigao Li, Kejin Chen, Dongchen Ji, Ming Zhang, Jinsong Wang
Cancer Res Treat. 2024;56(1):134-142.   Published online August 14, 2023
DOI: https://doi.org/10.4143/crt.2023.652
AbstractAbstract PDFPubReaderePub
Purpose
Tamoxifen showed individual differences in efficacy under different CYP2D6*10 genotypes. Our study evaluated the prognosis of tamoxifen or toremifene in hormone receptor (HR)–positive breast cancer patients under different genotypes.
Materials and Methods
CYP2D6*10 genotypes of HR-positive breast cancer patients were determined by Sanger sequencing, and all the patients were divided into tamoxifen group or toremifene group.
Results
A total of 268 patients with HR-positive breast cancer were studied. The median follow-up time was 72.0 months (range, 5.0 to 88.0 months). Of these, 88 (32.9%), 114 (42.5%), and 66 (24.6%) patients had C/C, C/T, and T/T genotypes, respectively. Among patients who received tamoxifen (n=176), the 5-year disease-free survival (DFS) rate in patients with C/C and C/T genotype was better than that in patients with T/T genotype, and the difference was statistically significant (p < 0.001 and p=0.030, respectively). In patients receiving toremifene, CYP2D6*10 genotype was not significantly associated with DFS (p=0.325). Regardless of genotypes, the 5-year DFS rate was higher in patients treated with toremifene than in patients with tamoxifen (91.3% vs. 80.0%, p=0.011). Compared with tamoxifen, toremifene remained an independent prognostic marker of DFS in multivariate analysis (hazard ratio, 0.422; p=0.021). For all the 180 patients with CYP2D6*10 C/T and T/T genotypes, the 5-year DFS rate was significantly higher in the toremifene group than in the tamoxifen group (90.8% vs. 70.1%, p=0.003).
Conclusion
Toremifene may be an alternative adjuvant endocrine therapy for patients with CYP2D6*10 mutant genotypes.

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  • FDA-approved drugs containing dimethylamine pharmacophore: a review of the last 50 years
    Sandeep Bindra, Kuntal Bose, Amrutha Chandran Thekkantavida, Della Grace Thomas Parambi, Tariq G. Alsahli, Manu Pant, Leena K. Pappachen, Hoon Kim, Bijo Mathew
    RSC Advances.2024; 14(38): 27657.     CrossRef
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Breast Cancer
Implications of Tamoxifen Resistance in Palbociclib Efficacy for Patients with Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: Subgroup Analyses of KCSG-BR15-10 (YoungPEARL)
Jiyun Lee, Seock-Ah Im, Gun Min Kim, Kyung Hae Jung, Seok Yun Kang, In Hae Park, Jee Hyun Kim, Hee Kyung Ahn, Yeon Hee Park
Cancer Res Treat. 2021;53(3):695-702.   Published online December 17, 2020
DOI: https://doi.org/10.4143/crt.2020.1246
AbstractAbstract PDFPubReaderePub
Purpose
YoungPEARL (KCSG-BR15-10) trial demonstrated a significant progression-free survival (PFS) benefit for premenopausal patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) metastatic breast cancer (MBC) for palbociclib plus exemestane with ovarian function suppression compared to capecitabine. However, the number of tamoxifen-sensitive premenopausal patients was small because most recurrences occurred early during adjuvant endocrine therapy (ET), with tamoxifen being the only drug used; hence, the data for these patients were limited. Here we present a subgroup analysis according to tamoxifen sensitivity from the YoungPEARL study. Materials and Methods Patients were randomized 1:1 to receive palbociclib+ET (oral exemestane 25 mg/day for 28 days, palbociclib 125 mg/day for 21 days, plus leuprolide 3.75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1,250 mg/m2 twice daily for 14 days every 3 weeks). Tamoxifen resistance was defined as: relapse while on adjuvant tamoxifen, relapse within 12 months of completing adjuvant tamoxifen, or progression while on first-line tamoxifen within 6 months for MBC.
Results
In total, 184 patients were randomized and 178 were included in the modified intention-to-treat population. PFS improvement in the palbociclib+ET group was observed in tamoxifen-sensitive patients (hazard ratio, 0.38; 95% confidence interval, 0.12 to 1.19). Furthermore, palbociclib+ET prolonged median PFS compared with capecitabine in tamoxifen-sensitive (20.5 months vs. 12.6 months) and tamoxifen-resistant (20.1 months vs. 14.5 months) patients. Palbociclib+ET demonstrated a higher rate of objective response, disease control, and clinical benefit in tamoxifen-sensitive patients. Conclusion This post hoc exploratory analysis suggests that palbociclib+ET is a promising therapeutic option for premenopausal HR+/HER2– MBC patients irrespective of tamoxifen sensitivity.

Citations

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  • Palbociclib plus endocrine therapy in hormone receptor-positive and HER2 negative metastatic breast cancer: a multicenter real-world study in the northwest of China
    Jiao Yang, Bing Zhao, Xiaoling Ling, Donghui Li, Jiuda Zhao, Yonggang Lv, Guangxi Wang, Xinlan Liu, Nanlin Li, Jin Yang
    BMC Cancer.2023;[Epub]     CrossRef
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Survival Outcome of Combined GnRH Agonist and Tamoxifen Is Comparable to That of Sequential Adriamycin and Cyclophosphamide Chemotherapy Plus Tamoxifen in Premenopausal Patients with Lymph-Node–Negative, Hormone-Responsive, HER2-Negative, T1-T2 Breast Cancer
Guiyun Sohn, Sei Hyun Ahn, Hee Jeong Kim, Byung-Ho Son, Jong Won Lee, Beom Seok Ko, Yura Lee, Sae Byul Lee, Seunghee Baek
Cancer Res Treat. 2016;48(4):1351-1362.   Published online April 6, 2016
DOI: https://doi.org/10.4143/crt.2015.444
AbstractAbstract PDFPubReaderePub
Purpose
The purpose of this study was to compare treatment outcomes between combined gonadotropin-releasing hormone agonist and tamoxifen (GnRHa+T) and sequential adriamycin and cyclophosphamide chemotherapy and tamoxifen (AC->T) in premenopausal patients with hormone-responsive, lymph-node–negative breast cancer.
Materials and Methods
In total, 994 premenopausal women with T1-T2, lymph-node–negative, hormone-receptor-positive, HER2-negative breast cancer between January 2003 and December 2008 were included in this retrospective cohort study. GnRHa+T and AC->T were administered to 608 patients (61.2%) and 386 patients (38.8%), respectively. Propensity score matching and inverse probability weighting were applied to the original cohort, and 260 patients for each treatment arm were included in the final analysis. Recurrence-free, cancer-specific, and overall survival was compared between the two treatment groups.
Results
A total of 994 patients were followed up for a median of 7.4 years (range, 0.5 to 11.4 years). The 5-year follow-up rate was 98.7%, and 13 patients were lost to follow-up. In propensity=matched cohorts (n=520), there was no difference in recurrence-free, cancer-specific, and overall survival rates between the two treatment groups (p=0.306, p=0.212, and p=0.102, respectively), and this was maintained after applying inverse probability weighting.
Conclusion
GnRHa+T is a reasonable alternative to AC-> T in patients with premenopausal, hormoneresponsive, HER2-negative, lymph-node–negative, T1-T2 breast cancer.

Citations

Citations to this article as recorded by  
  • Effectiveness of post-mastectomy adjuvant chemotherapy for the treatment of patients with prognostic stage IB breast cancer: A SEER-based study
    HongMei Wang, Yi Peng, Jianbin Wu, ZhuangWei Chen, HuaLe Zhang
    Asian Journal of Surgery.2023; 46(9): 3634.     CrossRef
  • Risk of recurrence among patients with HR-positive, HER2-negative, early breast cancer receiving adjuvant endocrine therapy: A systematic review and meta-analysis
    Elizabeth M. Salvo, Abril Oliva Ramirez, Jenilee Cueto, Ernest H. Law, Aaron Situ, Chris Cameron, Imtiaz A. Samjoo
    The Breast.2021; 57: 5.     CrossRef
  • Effectiveness of a 6-Month 22.5-mg Leuprolide Acetate Depot Formulation With Tamoxifen for Postoperative Premenopausal Estrogen Suppression in Hormone Receptor-Positive Breast Cancer
    Zhen-Yu Wu, Young-jin Lee, Heejeong Kim, Jongwon Lee, Il Yong Chung, Jisun Kim, Saebyeol Lee, Byung-Ho Son, Sung-Bae Kim, Jae Ho Jeong, Gyungyub Gong, Sei-Hyun Ahn, BeomSeok Ko
    Frontiers in Oncology.2021;[Epub]     CrossRef
  • Changes in bone mineral density during 5 years of adjuvant treatment in premenopausal breast cancer patients
    Minsung Kim, Hanna Kim, Sei Hyun Ahn, Vafa Tabatabaie, Sung Wook Choi, Guiyun Sohn, Sae Byul Lee, Beom Seok Ko, Il Yong Chung, Jisun Kim, Jong Won Lee, Byung Ho Son, Hee Jeong Kim
    Breast Cancer Research and Treatment.2020; 180(3): 657.     CrossRef
  • Change in Estradiol Levels among Premenopausal Patients with Breast Cancer Treated Using Leuprolide Acetate 11.25 Milligrams 3-Month Depot and Tamoxifen
    Young-jin Lee, Zhen-Yu Wu, Hee jeong Kim, Jong Won Lee, Il Yong Chung, Jisun Kim, Sae Byul Lee, Byung Ho Son, Sung-Bae Kim, Jae Ho Jung, Gyungyub Gong, Sei-Hyun Ahn, BeomSeok Ko
    Journal of Breast Cancer.2020; 23(5): 553.     CrossRef
  • Survival outcome of combined GnRH agonist and tamoxifen is comparable to that of sequential adriamycin and cyclophosphamide chemotherapy plus tamoxifen in premenopausal patients with early breast cancer
    Doonyapat Sa‑Nguanraksa, Thitikon Krisorakun, Wanee Pongthong, Pornchai O‑Charoenrat
    Molecular and Clinical Oncology.2019;[Epub]     CrossRef
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Effects of the Expression of Leptin and Leptin Receptor (OBR) on the Prognosis of Early-stage Breast Cancers
Yongnam Kim, Si-Young Kim, Jae Jin Lee, Jeongho Seo, Youn-Wha Kim, Suck Hwan Koh, Hwi-Joong Yoon, Kyung Sam Cho
Cancer Res Treat. 2006;38(3):126-132.   Published online June 30, 2006
DOI: https://doi.org/10.4143/crt.2006.38.3.126
AbstractAbstract PDFPubReaderePub
Purpose

Obesity-related leptin and leptin receptor (OBR) have a relation to the development of cancer and metastasis and also the low survival rate for breast cancer patients. Leptin has been associated with increased aromatase activity and it displays functional cross-talk with estrogen. This study was designed to determine the relationship between the expression of leptin and OBR in breast cancer tissue and the prognosis of early-stage breast cancer patients, and especially for the tamoxifen-treated patients.

Materials and Methods

Ninety-five patients with early-stage breast cancer and who had undergone surgical treatment at Kyung Hee University Hospital between January 1994 and June 2004 were analyzed. The surgical specimens underwent immunohistochemical analysis for leptin and OBR. The patients' survival and clinical characteristics were obtained from the medical records.

Results

Of the 95 patients, 79 (83%) and 32 (33.7%) showed the expression of leptin and OBR in breast cancer tissue, respectively. The expression of leptin and OBR in breast cancer tissue was not significantly related to the clinicopathological characteristics, including obesity, the expression of hormonal receptor, the HER-2/neu expression, menopause, stage and the nuclear grade. The expression of leptin and OBR was not significantly related to the overall disease-free survival (DFS). For the tamoxifen-treated postmenopausal obese patients, the DFS of the leptin-positive group was higher than that of the leptin-negative group (p=0.017).

Conclusion

The expression of leptin and OBR in breast cancer tissue may be not a prognostic factor for disease-free survival of breast cancer patients. In the future, further studies are needed to determine whether leptin expression could be a predictive factor for tamoxifen therapy in the postmenopausal obese subgroup among the early breast cancer patients.

Citations

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  • Exploring the multifaceted role of obesity in breast cancer progression
    Sooraj Kakkat, Prabhat Suman, Elba A. Turbat- Herrera, Seema Singh, Debanjan Chakroborty, Chandrani Sarkar
    Frontiers in Cell and Developmental Biology.2024;[Epub]     CrossRef
  • Greater Body Fatness Is Associated With Higher Protein Expression of LEPR in Breast Tumor Tissues: A Cross-Sectional Analysis in the Women’s Circle of Health Study
    Adana A.M. Llanos, John B. Aremu, Ting-Yuan David Cheng, Wenjin Chen, Marina A. Chekmareva, Elizabeth M. Cespedes Feliciano, Bo Qin, Yong Lin, Coral Omene, Thaer Khoury, Chi-Chen Hong, Song Yao, Christine B. Ambrosone, Elisa V. Bandera, Kitaw Demissie
    Frontiers in Endocrinology.2022;[Epub]     CrossRef
  • Roles and mechanisms of adipokines in drug resistance of tumor cells
    Yan Li, Chunyan Yu, Weimin Deng
    European Journal of Pharmacology.2021; 899: 174019.     CrossRef
  • Immunohistochemical analysis of adipokine and adipokine receptor expression in the breast tumor microenvironment: associations of lower leptin receptor expression with estrogen receptor-negative status and triple-negative subtype
    Adana A. M. Llanos, Yong Lin, Wenjin Chen, Song Yao, Jorden Norin, Marina A. Chekmareva, Coral Omene, Lei Cong, Angela R. Omilian, Thaer Khoury, Chi-Chen Hong, Shridar Ganesan, David J. Foran, Michael Higgins, Christine B. Ambrosone, Elisa V. Bandera, Kit
    Breast Cancer Research.2020;[Epub]     CrossRef
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    Tsung-Chieh Lin, Kuan-Wei Huang, Chia-Wei Liu, Yu-Chan Chang, Wei-Ming Lin, Tse-Yen Yang, Michael Hsiao
    Oncotarget.2018; 9(24): 17210.     CrossRef
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    Mohamad Nidal Khabaz, Amer Abdelrahman, Nadeem Butt, Lila Damnhory, Mohamed Elshal, Alia M. Aldahlawi, Swsan Ashoor, Basim Al-Maghrabi, Pauline Dobson, Barry Brown, Kaltoom Al-Sakkaf, Mohmmad Al-Qahtani, Jaudah Al-Maghrabi
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    Laetitia Delort, Adrien Rossary, Marie-Chantal Farges, Marie-Paule Vasson, Florence Caldefie-Chézet
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    Florence Caldefie-Chézet, Virginie Dubois, Laetitia Delort, Adrien Rossary, Marie-Paule Vasson
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  • Serum leptin level and waist-to-hip ratio (WHR) predict the overall survival of metastatic breast cancer (MBC) patients treated with aromatase inhibitors (AIs)
    Mehmet Artac, Hakan Bozcuk, Aysel Kıyıcı, Orhan Onder Eren, Melih Cem Boruban, Mustafa Ozdogan
    Breast Cancer.2013; 20(2): 174.     CrossRef
  • Leptin attenuates the anti-estrogen effect of tamoxifen in breast cancer
    Xiaofeng Chen, Xiaoming Zha, Wei Chen, Tingting Zhu, Jinrong Qiu, Oluf Dimitri Røe, Jun Li, Zhaoxia Wang, Yongmei Yin
    Biomedicine & Pharmacotherapy.2013; 67(1): 22.     CrossRef
  • The role of leptin receptor gene polymorphisms in determining the susceptibility and prognosis of NSCLC in Chinese patients
    Yuliang Li, Jianli Geng, Yongzheng Wang, Qinghua Lu, Yimeng Du, Wujie Wang, Zheng Li
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    Mehmet Artac, Kadri Altundag
    Medical Oncology.2012; 29(3): 1510.     CrossRef
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Effects of Polyamines on TNFalpha- or Tamoxifen-induced Apoptosis in Human Breast Cancer Cells
Ji Young Kim, Ki Young Kim, Kyeong Hee Lee, Ki Whan Hong, Byeong Gee Kim
Cancer Res Treat. 2001;33(5):385-391.   Published online October 31, 2001
DOI: https://doi.org/10.4143/crt.2001.33.5.385
AbstractAbstract PDF
PURPOSE
To investigate the effects of polyamines on tumor necrosis factor alpha (TNFalpha)-or tamoxifen (TAM)-induced apoptosis in estrogen receptor (ER)-positive MCF- 7 and ER-negative MDA-MB-231 human breast cancer cells.
MATERIALS AND METHODS
Cell viability was assessed by using MTT assay. Reactive oxygen species (ROS) generation was measured using 2', 7'-dichlorofluorescin diacetste (DCFDA) by fluorescence plate reader. DNA fragmentation was assessed by 1.5% agarose gel electrophoresis.
RESULTS
TNFalpah and TAM showed significant dose- and time- dependent inhibitory effects on the growth of MCF-7 human cells. However, the growth of MDA-MB-231 cells were not inhibited by TNFalpha or TAM treatment. The generation of ROS was increased in dose-and time-dependent manner by TNFalpha treatment in MCF-7 cells. Polyamines, especially spermine suppressed TNFalpha-induced ROS generation in MCF-7 cells. Antioxidant effects of polyamines were also demonstrated by DNA fragmentation, cell morphology as well as ROS generation assay. Polyamines also blocked TAM-induced cell death in MCF-7 cell. However, MDA-MB-231 cells showed resistance to the cytotoxic effects of TNFalpha or TAM.
CONCLUSION
These results suggest that polyamines may prevent TNFalpha or TAM-induced apoptosis in MCF-7 human breast cancer cells.

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  • Influence of Estrogen and Polyamines on Mifepristone-induced Apoptosis in Prostate Cancer Cells
    Eun Kyung Choi, Hwi-June Song, Min S. Park, Byeong Gee Kim
    Cancer Research and Treatment.2004; 36(1): 85.     CrossRef
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The Effect of Long-term Tamoxifen Therapy on Endometrium Evaluated by Transvaginal Sonography in Postmenopausal Women Undergone Breast Cancer Surgery
Jung Hoon Bae, Lee Su Kim, Jeong Jin Kim, Min Kyun Lim, Jong Hyun Kim, Young Min Woo, Man Chul Park, Dong Kun Kim, Chang Sig Choi, Sung Kim
J Korean Cancer Assoc. 2000;32(3):539-544.
AbstractAbstract PDF
PURPOSE
Tamoxifen is a non-steroidal antiestrogenic drug used mainly in the adjuvant therapy of breast cancer and it also has estrogenic effect to the endometrium. We investigated the effects of tamoxifen on endometrial thickening in postmenopausal women taking adjuvant tamoxifen therapy for breast cancer, and analyzed the correlation between sonographic findings, pathologic findings and duration of tamoxifen therapy.
MATERIALS AND METHODS
Forty three patients previously operated and being treated by tamoxifen since July 1995 to August 1999 were involved in this study. Control group was selected from patients of postmenopausal syndrome visiting postmenopausal clinic more than 2 years after menopause since January 1994 to August 1997. Endometrial thicknesses of breast cancer patients taking tamoxifen were measured twice a year for 2 years and then once a year by transvaginal ultrasonography. They were considered abnormal when those thicknesses were greater than 6 mm. Sonographic mearsurements of control patients were done once at the first visit and which were compared with those of breast cancer patients.
RESULTS
The mean endometrial thicknesses of breast cancer patients receiving tamoxifen therapy were 5.06 mm (4.86~5.21 mm) at 6th month, 5.1 mm (4.92~6.00 mm) at 12th month, 5.13 mm (4.89~5.32 mm) at 18th month, 5.15 mm (4.97~5.28 mm) at 24th month and 5.14 mm (4.96~5.21 mm) at 36th month. The mean thickness of control patients was 4.87 mm. The mean endometrial thickness of breast cancer patients and that of control patients were 5.07 mm and 4.87 mm respectively. Only one patient with stage I breast cancer showed endometrial thicknessof 6 mm during follow-up and endometrial biopsy showed atypical endometrial hyperplasia. Endometrial thickness significantly increased after 18 months of tamoxifen therapy, but the rate of increase was slow.
CONCLUSION
The endometrial thickness increased with duration of tamoxifen therapy, but the rate of increase was slow and seldom exceeded 6 mm. So we concluded the risk of endometrial cancer is low.
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The Role of bcl-2 and p53 in Tamoxifen-Induced Apoptosis of Human Breast Cancer Cell Lines
Woo Chul Noh, Dong Young Noh, Yong Ho Ham, Chang Min Kim, Nam Sun Paik, Nan Mo Moon, Kuk Jin Choe
J Korean Cancer Assoc. 2000;32(3):531-538.
AbstractAbstract PDF
PURPOSE
Tamoxifen has been well known as an effective anti-tumor agent against breast cancer. The important role of bcl-2 and p53 proteins in tamoxifen-induced apoptosis of breast cancer cells has been suggested. However, the paradoxical fact that bcl-2 over-expression is assdegrees Ciated with better prognosis in clinic has not yet been clearly explained. To investigate this paradox, we analyzed the effect and dynamics of bcl-2 and p53 on the apoptosis after treatment of breast cancer cells with tamoxifen.
MATERIALS AND METHODS
The human breast cancer cell lines MCF-7 and MB MDA-468 were treated with 17-betaestradiol (E2) and tamoxifen.
RESULTS
Following tamoxifen treatment, MCF-7 cells underwent apoptosis accompanied by reduced bcl-2 expression. E2 pre-treatment led to the inhibition of tamoxifen-mediated apoptosis and bcl-2 down-regulation. When MB MDA-468 cells were treated with E2 or tamoxifen, bcl-2 and p53 protein expression did not change and apoptosis did not develop.
CONCLUSION
We observed that the down-regulation of bcl-2 by tamoxifen treatment can facilitate the apoptosis of breast cancer cells without p53 mutations. This finding was consistent with clinical experiences in which bcl-2 positive tumors were assdegrees Ciated with more indolent phenotypes in breast cancer.
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Restoration of Hormone Dependency in Estrogen Receptor - Lipofected MDA-MB-231 Human Breast Cancer Cells
Young Jin Suh, Jae Hee Chang, Chung Soo Chun
J Korean Cancer Assoc. 1999;31(3):473-482.
AbstractAbstract PDF
PURPOSE
The loss of estrogen and progesterone receptors appeats to be associated with a progression to less differentiated and hormone-independent tumors. The gain of hormone independency over time even in estrogen receptor-positive tumors has become another obstacle to endocrine therapy for breast cancer. We tried to regain the hormone dependency in estrogen receptor-negative breast cancer cells by lipofecting estmgen receptor cDNA.
MATERIALS AND METHODS
The mutant human estrogen receptor cDNA (pSGS-HEO) was lipofected into estrogen receptor-negative human breast cancer cell line MDA-MB-231, in an attempt to restore their sensitivity to antiestrogen. Then the effects of 17p-estradiol and tamoxifen were studied by counting viable cell numbers after treating the lipofected cell line with either one or together.
RESULTS
Culture medium cantaining phenol red, a weak estrogen, has growth advantages compared with culture medium without it. In both culture conditions, cell growth was most profoundly inhibited in 4 days after lipofection with mutant human estrogen receptor cDNA, which was overcome after that day. Tamoxifen, as an antiestrogen, showed a growth inhibitory effect slightly stronger tban combined conditions of tamoxifen and 17- estradiol compared to estrogen-treated group and to control, and the inhibitory effect was lasted 4 days.
CONCLUSION
The temporary induction of estrogen receptor by lipofection with pSGS-HEO on estrogen receptor-negative human breast cancer cell line MDA-MB-231 showed negative growth control on these cells by tamoxifen, indicating that liposome-mediated estrogen receptor transfection may be used as a novel therapeutic strategy for hormane independent human breast cancers in the near future.
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Reversal of ( MDR ) Multidrug resistance ) in Adiamycin - Resistant MCF - 7 Cells by Tamoxifen : Possible Role of Protedin Kinase ( PCK )
Han Lim Moon, Hoon Kyo Kim, Kyung Shik Lee
J Korean Cancer Assoc. 1994;26(2):242-249.
AbstractAbstract PDF
Introduction: MDR(multidrug resistance), which is caused by mdr gene and its product, p-gly- coprotein, is one of the most important obstacles during cancer chemtherapy. Recently, many efforts to reverse MDR have been done and partly applied in clinic. Verapamil, quinidine, dipyridamole and cyclosporine were the representative ones and tamoxifen and toremifene have been known as those kinds. On the other hand, protein kinase c(PKC) has a critical role in cell proliferation and differentiation and also associated with MDR. Using wild type and adriamycin-resistant type of MCF-7(MCF-7/WT and MCF-7/ADM), we found antiestrogen, tamoxifen, had a synergistic cytotoxic effect with adriamycin on MCF-7/ADM, not on MCF-1/ WT. We also tried to clarify the mechanisms of synergism of tamoxifen with adriamycin, espe- cially in the viewpoint of drug uptake and PKC activity. Results: IC of adriamycin-cytotoxicity on MCF-7/WT and MCF-7/ADM was 0.2 ug/ml and 2 ug/ml, respectively. Tamoxifen moved IC of adriamycin-cytotoxicity of left in a dose-dependent manner in MCF-7/ADM, and 10 pM concentration of tamoxifen made IC 0.2 pg/ml in that cell line, which was very similar to IC in MCF-7/WT. But tamoxifen did not have synergistic cytotoxicity with adriamycin on MCF-7/WT. In drug efflux study with C14-adriamycin, tamoxifen enhanced drug uptake more than 200% in MCF-7/ADM although it markedly decreased when tamoxifen was added. There was no difference in baseline PKC activity and degree of dose-dependent inhibition on PKC activity by adriamycin in those two cell lines. Canclusion; Tamoxifen is thought to be as one of the plausible agents to reverse MDR in breast cancer. The possible mechanisms are to increase cellular uptake of adriamycin and to inhibit PKC activity.
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Transforming growth Factor - beta ( TGF-β ) as a Mediator of Tamoxifen and Retinoic Acid in Breast Carcer
Hy Do Lee, Dong Sup Yoon, Chul Woon Jung, Ja Yun Koo
J Korean Cancer Assoc. 1996;28(3):443-451.
AbstractAbstract PDF
TGF-¥a is multifunctional regulatory homodimeric polypeptides and reaulate cell differentiation, cell growth, cell function and is the most potent growth-inhibitory polypeptides known for a wide variety of cell types including most normal and transformed epithelial, endothelial, fibroblast, lymphoid and hematopoietic cells. The production of TGF-¥a by the estrogen receptor-positive cell line MCF-7 has been reported to be most affected by antiestrogens, and Tamoxifen caused a 5-fold increase in production of TGF-¥a by MCF-7 cells and its regulation of TGF-¥a production was thought to be posttranscriptional. Recent work has shown that the proliferation of both mouse and human keratinacytes was potentially and reversibly inhibited by TGF-¥a, and that retinoic acid induced TGF-¥a1 in cultured keratinocytes and mouse epidermis. These results suggest that the regulation of TGF-¥a2, expression by tamoxifen and retinoic acid may have a important role in control of breast cancer cell growth. To obtain better understanding of how tamoxifen and retinoic acid could regulate growth of breast cancer cells, we carried out this experimental study. Using phenol red-free medium, we cultured MCF-7 cells and then treated with various dosage of tamoxifen, retinoic acid and tamoxifen with retinoic acid, and then observed MCF-7 cell growth and the production of TGF-¥a. The growth of MCF-7 cell was markedly inhibited by tamoxifen, and synergistic inhibitory effect was discovered when retinoic acid was supplemented with tamoxifen. Both tamoxifen and retinoic acid increased the secretion of TGF-¥a1, & TGF-¥a2, especially TGF-¥a2. The mRNA induction of TGF-¥a2 was increased by treatment of retinoic acid and it was more increased by treatment of retinoic acid with tamoxifen. As these results, we concluded that Tamoxifen and retinoic acid increased the production of the TGF-¥a2 retinoic acid may be used as second postoperative adjuvant therapeutic agent of breast cancer.
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