scholarly journals SET Overexpression is Associated with Worse Recurrence-Free Survival in Patients with Primary Breast Cancer Receiving Adjuvant Tamoxifen Treatment

2018 ◽  
Vol 7 (9) ◽  
pp. 245 ◽  
Author(s):  
Yu-Hsiang Huang ◽  
Pei-Yi Chu ◽  
Ji-Lin Chen ◽  
Chun-Teng Huang ◽  
Chia-Han Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Phosphatase ◽  
Tamoxifen Treatment ◽  
Adjuvant Tamoxifen ◽  
Recurrence Free Survival ◽  
Free Survival ◽  
Er Positive ◽  
Phosphatase 2A ◽  
Positive Breast Cancer

Adjuvant tamoxifen reduces the recurrence rate of estrogen receptor (ER)-positive breast cancer. Previous in vitro studies have suggested that tamoxifen can affect the cancerous inhibitor of protein phosphatase 2A (CIP2A)/protein phosphatase 2A (PP2A)/phosphorylation Akt (pAkt) signaling in ER-negative breast cancer cells. In addition to CIP2A, SET nuclear proto-oncogene (SET) oncoprotein is another intrinsic inhibitor of PP2A, participating in cancer progression. In the current study, we explored the clinical significance of SET, CIP2A, PP2A, and Akt in patients with ER-positive breast cancer receiving adjuvant tamoxifen. A total of 218 primary breast cancer patients receiving adjuvant tamoxifen with a median follow-up of 106 months were analyzed, of which 17 (7.8%) experienced recurrence or metastasis. In an immunohistochemical (IHC) stain, SET overexpression was independently associated with worse recurrence-free survival (RFS) (hazard ratio = 3.72, 95% confidence interval 1.26–10.94, p = 0.017). In silico analysis revealed mRNA expressions of SET, PPP2CA, and AKT1 significantly correlated with worse RFS. In vitro, SET overexpression reduced tamoxifen-induced antitumor effects and drove luciferase activity in an Estrogen receptor element (ERE)-dependent manner. In conclusion, SET is a prognostic biomarker in patients with primary ER-positive breast cancer receiving adjuvant tamoxifen and may contribute to the failure of the tamoxifen treatment by modulating the ER signaling. Our study warrants further investigation into the potential role of SET in ER-positive breast cancer.

scholarly journals NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1633
Author(s):  
Yu Cheon Kim ◽  
Clara Yuri Kim ◽  
Ji Hoon Oh ◽  
Myoung Hee Kim
Keyword(s):  
Breast Cancer ◽  
Tamoxifen Resistance ◽  
Erk Signaling ◽  
Tamoxifen Treatment ◽  
Loss Of Function ◽  
Mcf7 Cells ◽  
Er Positive ◽  
Tamoxifen Resistant ◽  
Positive Breast Cancer

Endocrine therapy is used to treat estrogen receptor (ER)-positive breast cancer. Tamoxifen is effective against this cancer subtype. Nonetheless, approximately 30% of patients treated with tamoxifen acquire resistance, resulting in therapeutic challenges. NR4A1 plays key roles in processes associated with carcinogenesis, apoptosis, DNA repair, proliferation, and inflammation. However, the role of NR4A1 in tamoxifen-resistant ER-positive breast cancer has not yet been elucidated. Here, we propose that NR4A1 is a promising target to overcome tamoxifen resistance. NR4A1 gene expression was downregulated in tamoxifen-resistant MCF7 (TamR) cells compared to that in MCF7 cells. Kaplan-Meier plots were used to identify high NR4A1 expression correlated with increased survival rates in patients with ER-positive breast cancer following tamoxifen treatment. Gain and loss of function experiments showed that NR4A1 restores sensitivity to tamoxifen by regulating cell proliferation, migration, invasion, and apoptosis. NR4A1 localized to the cytoplasm enhanced the expression of apoptotic factors. In silico and in vitro analyses revealed that NR4A1 enhanced responsiveness to tamoxifen by suppressing ERK signaling in ER-positive breast cancer, suggesting that the NR4A1/ERK signaling axis modulates tamoxifen resistance. These results indicate that NR4A1 could be a potential therapeutic target to overcome tamoxifen resistance in ER-positive breast cancer.

scholarly journals Differential expression of protein phosphatase 2A activator in cancers of the breast.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Differential Expression ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Normal Breast ◽  
Recurrence Free Survival ◽  
Significant Differential Expression ◽  
Primary Tumors ◽  
Free Survival ◽  
Phosphatase 2A

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding protein phosphatase 2A activator, PPP2R4, also known as PTPA (protein phosphatase 2 phosphatase activator) when comparing primary tumors of the breast to the tissue of origin, the normal breast. PPP2R4 mRNA was present at significantly higher quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of PPP2R4 in primary tumors of the breast was correlated with recurrence-free survival in patients with basal and luminal B type cancers, but in a contrary manner, demonstrating a complex relationship between correlation of primary tumor expression with recurrence-free survival based on molecular subtype. PPP2R4 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

scholarly journals Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 771
Author(s):  
Tessa A. M. Mulder ◽  
Mirjam de With ◽  
Marzia del Re ◽  
Romano Danesi ◽  
Ron H. J. Mathijssen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Plasma Concentrations ◽  
Tamoxifen Treatment ◽  
Current Status ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Er Positive ◽  
Positive Breast Cancer

Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate.

scholarly journals Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update

2014 ◽  
Vol 32 (21) ◽  
pp. 2255-2269 ◽  
Author(s):  
Harold J. Burstein ◽  
Sarah Temin ◽  
Holly Anderson ◽  
Thomas A. Buchholz ◽  
Nancy E. Davidson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Practice ◽  
Aromatase Inhibitor ◽  
Endocrine Therapy ◽  
Clinical Practice Guideline ◽  
Adjuvant Endocrine Therapy ◽  
Tamoxifen Treatment ◽  
Adjuvant Tamoxifen ◽  
Hormone Receptor Positive ◽  
Positive Breast Cancer

PurposeTo update the ASCO clinical practice guideline on adjuvant endocrine therapy on the basis of emerging data on the optimal duration of treatment, particularly adjuvant tamoxifen.MethodsASCO convened the Update Committee and conducted a systematic review of randomized clinical trials from January 2009 to June 2013 and analyzed three historical trials. Guideline recommendations were based on the Update Committee's review of the evidence. Outcomes of interest included survival, disease recurrence, and adverse events.ResultsThis guideline update reflects emerging data on duration of tamoxifen treatment. There have been five studies of tamoxifen treatment beyond 5 years of therapy. The two largest studies with longest reported follow-up show a breast cancer survival advantage with 10-year durations of tamoxifen use. In addition to modest gains in survival, extended therapy with tamoxifen for 10 years compared with 5 years was associated with lower risks of breast cancer recurrence and contralateral breast cancer.RecommendationsPrevious ASCO guidelines recommended treatment of women who have hormone receptor–positive breast cancer and are premenopausal with 5 years of tamoxifen, and those who are postmenopausal a minimum of 5 years of adjuvant therapy with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor (in sequence). If women are pre- or perimenopausal and have received 5 years of adjuvant tamoxifen, they should be offered 10 years total duration of tamoxifen. If women are postmenopausal and have received 5 years of adjuvant tamoxifen, they should be offered the choice of continuing tamoxifen or switching to an aromatase inhibitor for 10 years total adjuvant endocrine therapy.

scholarly journals HOXA5 Expression Is Elevated in Breast Cancer and Is Transcriptionally Regulated by Estradiol

2020 ◽  
Vol 11 ◽  
Author(s):  
Imran Hussain ◽  
Paromita Deb ◽  
Avisankar Chini ◽  
Monira Obaid ◽  
Arunoday Bhan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Female Rats ◽  
Er Positive ◽  
Gene Regulatory ◽  
Cancer Tissues ◽  
Positive Breast Cancer

HOXA5 is a homeobox-containing gene associated with the development of the lung, gastrointestinal tract, and vertebrae. Here, we investigate potential roles and the gene regulatory mechanism in HOXA5 in breast cancer cells. Our studies demonstrate that HOXA5 expression is elevated in breast cancer tissues and in estrogen receptor (ER)-positive breast cancer cells. HOXA5 expression is critical for breast cancer cell viability. Biochemical studies show that estradiol (E2) regulates HOXA5 gene expression in cultured breast cancer cells in vitro. HOXA5 expression is also upregulated in vivo in the mammary tissues of ovariectomized female rats. E2-induced HOXA5 expression is coordinated by ERs. Knockdown of either ERα or ERβ downregulated E2-induced HOXA5 expression. Additionally, ER co-regulators, including CBP/p300 (histone acetylases) and MLL-histone methylases (MLL2, MLL3), histone acetylation-, and H3K4 trimethylation levels are enriched at the HOXA5 promoter in present E2. In summary, our studies demonstrate that HOXA5 is overexpressed in breast cancer and is transcriptionally regulated via estradiol in breast cancer cells.

scholarly journals 17β-estradiol-containing liposomes as a novel delivery system for the antisense therapy of ER-positive breast cancer: An in vitro study on the MCF-7 cell line

2014 ◽  
Vol 33 (2) ◽  
pp. 921-929 ◽  
Author(s):  
ZBYNEK HEGER ◽  
JAROMIR GUMULEC ◽  
NATALIA CERNEI ◽  
KATERINA TMEJOVA ◽  
PAVEL KOPEL ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Delivery System ◽  
In Vitro Study ◽  
Antisense Therapy ◽  
Er Positive ◽  
17Β Estradiol ◽  
Mcf 7 ◽  
Positive Breast Cancer

scholarly journals Concordance of immunohistochemistry based and gene expression-based subtyping in breast cancer

2020 ◽  
Author(s):  
Johanna Holm ◽  
Nancy Yiu-Lin Yu ◽  
Annelie Johansson ◽  
Alexander Ploner ◽  
Per Hall ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Distant Recurrence ◽  
Tamoxifen Treatment ◽  
Survival Models ◽  
Recurrence Free Survival ◽  
Luminal A ◽  
Ki 67 ◽  
Treatment Benefit ◽  
Free Survival ◽  
Cancer Subtypes

Abstract Background Use of immunohistochemistry (IHC) based surrogates of molecular breast cancer subtypes is common in research and clinical practice, but information on their comparative validity and prognostic capacity is scarce. Methods Data from two PAM50-subtyped Swedish breast cancer cohorts were used; STO-3 with 561 patients diagnosed 1976-1990, and Clinseq with 237 patients diagnosed 2005-2012. We evaluated three surrogate classifications; the IHC3 surrogate classifier based on ER/PR/HER2, and the StGallen and Prolif surrogate classifiers also including Ki-67. Accuracy, kappa, sensitivity and specificity were computed as compared to PAM50. Alluvial diagrams of misclassification patterns were plotted. Distant recurrence-free survival was assessed using Kaplan-Meier plots, and tamoxifen treatment benefit for luminal subtypes was modeled using flexible parametric survival models. Results The concordance with PAM50 ranged from poor to moderate (kappa = 0.36–0.57, accuracy = 0.54-0.75), with best performance for the Prolif surrogate classification in both cohorts. Good concordance was only achieved when luminal subgroups were collapsed (kappa = 0.71- 0.69, accuracy = 0.90-0.91). The StGallen surrogate classification misclassified luminal A into luminal B, the reverse pattern was seen with the others. In distant recurrence-free survival, surrogates were more similar to each other than PAM50. The difference in tamoxifen treatment benefit between luminal A and B for PAM50 was not replicated with any surrogate classifier. Conclusions All surrogate classifiers had limited ability to distinguish between PAM50 luminal A and B, but patterns of misclassifications differed. PAM50 subtyping appeared to yield larger separation of survival between luminal subtypes than any of the surrogate classifications.

scholarly journals In vitro study of anti-ER positive breast cancer effect and mechanism of 1,2,3,4-6-pentyl-O-galloyl-beta-d-glucose (PGG)

2019 ◽  
Vol 111 ◽  
pp. 813-820 ◽  
Author(s):  
Qiu Xiang ◽  
Juan Tang ◽  
Qin Luo ◽  
Jinfeng Xue ◽  
Yexing Tao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
In Vitro Study ◽  
Vitro Study ◽  
Er Positive ◽  
Positive Breast Cancer
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