scholarly journals Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response

2010 ◽  
Vol 17 (1) ◽  
pp. 215-230 ◽  
Author(s):  
Ton van Agthoven ◽  
Anieta M Sieuwerts ◽  
Danielle Meijer ◽  
Marion E Meijer-van Gelder ◽  
Thecla L A van Agthoven ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Clinical Relevance ◽  
Advanced Disease ◽  
Tamoxifen Treatment ◽  
Endocrine Treatment ◽  
Mrna Levels ◽  
Tumor Aggressiveness ◽  
Breast Cancer Patients ◽  
Genetic Screens

Although endocrine treatment of breast cancer is effective and common practice, in advanced disease the development of resistance is nearly inevitable. To get more insight into individual genes that account for resistance against hormonal agents, we have executed functional genetic screens and subsequently evaluated the clinical relevance of several identified genes with respect to tumor aggressiveness and tamoxifen resistance in estrogen receptor-positive patients. Estrogen-dependent human breast cancer cells were transduced with different retroviral cDNA expression libraries and subjected to selective cultures with various anti-estrogens. From a total of 264 resistant cell clones, 132 different genes were recovered by PCR. By applying stringent selection criteria, we identified 15 breast cancer anti-estrogen resistance (BCAR) genes individually yielding resistance. BCAR genes were recovered with differential frequencies for the diverse culture conditions and anti-estrogen drugs. Analysis of the relation of BCAR genes (EIF1, FBXL10, HRAS, NRG1, PDGFRA, PDGFRB, RAD21, and RAF1) with tamoxifen treatment in patients with advanced disease showed significant association with clinical benefit and progression-free survival for EIF1 and PDGFRA mRNA levels. Furthermore, PDGFRA and HRAS mRNA levels were significantly associated with tumor aggressiveness in lymph node-negative patients who had not received adjuvant systemic therapy. In conclusion, our functional genetic screens showed that BCAR genes differ in their ability to confer resistance towards distinct anti-estrogens. Based on the clinical relevance of several BCAR genes, further studies are warranted to characterize the underlying mechanisms, which may ultimately lead to the development of novel treatments and more individualized management of breast cancer patients.

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 Enhancers mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer

2017 ◽  
Author(s):  
Darren K. Patten ◽  
Giacomo Corleone ◽  
Balázs Győrffy ◽  
Edina Erdős ◽  
Alina Saiakhova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Regulatory Elements ◽  
Phenotypic Heterogeneity ◽  
Endocrine Treatment ◽  
Clinical Samples ◽  
Luminal Breast Cancer ◽  
Breast Cancer Patients ◽  
Expression Of Genes

AbstractThe degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumour evolution is poorly understood. Phenotypic divergence can be achieved via the inheritance of alternative transcriptional programs1,2. Cell-type specific transcription is maintained through the activation of epigenetically-defined regulatory regions including promoters and enhancers1,3,4. In this work, we annotated the epigenome of 47 primary and metastatic oestrogen-receptor (ERα)-positive breast cancer specimens from clinical samples, and developed strategies to deduce phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Highly shared regions contain a unique set of regulatory information including the motif for the transcription factor YY1. In vitro work shows that YY1 is essential for ERα transcriptional activity and defines the critical subset of functional ERα binding sites driving tumor growth in most luminal patients. YY1 also control the expression of genes that mediate resistance to endocrine treatment. Finally, we show that H3K27ac levels at active enhancer elements can be used as a surrogate of intra-tumor phenotypic heterogeneity, and to track expansion and contraction of phenotypic subpopulations throughout breast cancer progression. Tracking YY1 and SLC9A3R1 positive clones in primary and metastatic lesions, we show that endocrine therapies drive the expansion of phenotypic clones originally underrepresented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.

scholarly journals AGR2 Predicts Tamoxifen Resistance in Postmenopausal Breast Cancer Patients

2013 ◽  
Vol 35 ◽  
pp. 207-212 ◽  
Author(s):  
Roman Hrstka ◽  
Veronika Brychtova ◽  
Pavel Fabian ◽  
Borivoj Vojtesek ◽  
Marek Svoboda
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Optimal Algorithm ◽  
Endocrine Resistance ◽  
Postmenopausal Breast Cancer ◽  
Progression Free Survival ◽  
Tamoxifen Treatment ◽  
Mrna Levels ◽  
Breast Cancer Patients ◽  
Er Positive

Endocrine resistance is a significant problem in breast cancer treatment. Thus identification and validation of novel resistance determinants is important to improve treatment efficacy and patient outcome. In our work, AGR2 expression was determined by qRT-PCR in Tru-Cut needle biopsies from tamoxifen-treated postmenopausal breast cancer patients. Our results showed inversed association of AGR2 mRNA levels with primary treatment response (P=0.0011) and progression-free survival (P=0.0366) in 61 ER-positive breast carcinomas. As shown by our experimental and clinical evaluations, elevated AGR2 expression predicts decreased efficacy of tamoxifen treatment. From this perspective, AGR2 is a potential predictive biomarker enabling selection of an optimal algorithm for adjuvant hormonal therapy in postmenopausal ER-positive breast cancer patients.

scholarly journals Altered Sirtuin 7 Expression is Associated with Early Stage Breast Cancer

2015 ◽  
Vol 9 ◽  
pp. BCBCR.S23156 ◽  
Author(s):  
Ahmad Aljada ◽  
Ayman M. Saleh ◽  
Moath Alkathiri ◽  
Heba Bani Shamsa ◽  
Ahmad Al-Bawab ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mrna Expression ◽  
Cancer Progression ◽  
Early Stage ◽  
Cdna Array ◽  
Normal Breast ◽  
Mrna Levels ◽  
Breast Cancer Patients ◽  
Cancer Disease ◽  
Expression Status

Background To evaluate sirtuin-7 (SirT7) mRNA expression status in breast cancer patients with different metastatic stages and survey SirT7 mRNA expression status in eight different types of cancer. Methods The expression of SirT7 in the commercially available TissueScan qPCR Breast Cancer Disease cDNA arrays containing 16 normal, 23 Stage I, 36 IIA, 22 IIB, 8 IIIA, 23 IIIA, 6 IIIB, 13 IIIC, and 5 IV were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) assay. Similar analysis was performed in TissueScan qPCR Cancer Survey cDNA array, which includes breast, colon, kidney, liver, lung, ovarian, prostate, and thyroid specimens. Results The mRNA expression levels of SirT7 were significantly higher in breast cancer samples compared to normal breast specimens ( P < 0.001). Stratification of patients into groups according to metastatic stages indicated statistically significantly higher levels of SirT7 mRNA in CS-I, CS-II, and CS-III when compared to normal breast tissue ( P < 0.05). Notably, SirT7 mRNA levels were higher in CS-I, CS-IIA, CS-IIB, and CS-IIIA ( P < 0.05). Additionally, there were significantly lower SirT7 mRNA levels in thyroid carcinoma when compared to their corresponding normal tissue ( P < 0.05). Conclusions Our results indicate an increase in the mRNA expression level of SirT7 in breast cancer, particularly in CS-I, CS-IIA, CS-IIB, and CS-IIIA. The relationship of altered SirT7 with breast cancer progression and patient survival should be prospectively explored in future studies.

scholarly journals A Novel Melatonergic Signature Predicts Reccurence Risk and Therapeutic Response in Breast Cancer Patients

2018 ◽  
Author(s):  
Hoa Quynh Tran ◽  
Phuc Loi Luu ◽  
Van Thai Than ◽  
Declan Clarke ◽  
Hanh Ngoc Lam ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Expression Profiles ◽  
Endocrine Resistance ◽  
Low Risk ◽  
Tamoxifen Treatment ◽  
Breast Cancer Patients ◽  
Survival Times ◽  
Free Survival

AbstractASMT is a key determinant of the levels of released melatonin. Though melatonin has been shown to exhibit anti-cancer activity and prevents endocrine resistance in breast cancer, the role of ASMT in breast cancer progression remains unclear. In this retrospective study, we analyzed gene expression profiles from thousands of patients and found thatASMTexpression was significantly lower in breast cancer tumors relative to healthy tissue. Among cancer patients, those with greater expression had better relapse-free survival outcomes and longer metastasis-free survival times, and they also experienced longer periods before relapse or distance recurrence following tamoxifen treatment. Administration of melatonin, in combination with tamoxifen, further promoted cancer cell death by promoting apoptosis. Motivated by these results, we devised an ASMT gene signature that identifies low-risk cases with great accuracy. This signature was validated using both mRNA array and RNAseq datasets. Intriguingly, patients who are classified as high-risk benefit from adjuvant chemotherapy, and those with grade II tumors who are classified as low-risk exhibit improved overall survival and distance relapse-free outcomes following endocrine therapy. Our findings more clearly elucidate the roles ofASMT,provide strategies for improving the efficacy of tamoxifen treatment, and help to identify those patients who may maximally benefit from adjuvant or endocrine therapies.

Diagnostic Value of VDR in Bone Metastasis and Prognosis of Patients with Breast Cancer and Expression Correlation between VDR and Hr

2021 ◽  
Author(s):  
Pan Ding ◽  
XiaoMing Du ◽  
LiHui Wan ◽  
Xueke Zhao ◽  
DeRui Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Diagnostic Value ◽  
Normal Breast ◽  
Mrna Levels ◽  
Breast Cancer Patients ◽  
Protein Levels ◽  
Low Expression

Background: Breast cancer is more likely to metastasize to the bone. Previous researches have revealed that vitamin D receptor (VDR) contributes to breast cancer progression and bone metastasis in mouse and human breast cells, and Hairless (Hr) protein interacts with VDR in the mammalian hair cycle. This study aimed to explore the expression of VDR/Hr in breast cancer, and the correlation between VDR/Hr and prognosis, bone metastasis, and metastasis-related prognosis. Methods: The expression of VDR and Hr was performed on 119 breast cancer tissues and corresponding normal breast tissue from each of the breast cancer samples by Immunohistochemistry (IHC) staining, and the databases were supplemented as well. Results: The expression of VDR protein was significantly decreased in breast cancer patients (p < 0.05), inversely, the UALCAN (p = 0.000) and GEPIA (p > 0.05) databases showed VDR mRNA expression tended to be higher in tumor tissues. Hr protein was expressed at low level within breast cancer specimens (p < 0.05), which was in agreement with the level of Hr mRNA in the UALCAN (p = 0.005) and GEPIA (p > 0.05). The protein levels of VDR and Hr were positively correlated (p > 0.05), while the mRNA levels suggested a closely relationship in the GEPIA (p < 0.05). Low expression of Hr protein displayed a tendency for longer overall survival (OS) and recurrence-free survival (RFS), and its mRNA data also revealed the same trend in the KM dataset (both p > 0.05). Whereas, VDR protein and mRNA low expression had markedly shorter OS and RFS (both p < 0.05). The down-regulation of VDR protein was significantly associated with advanced stage (p < 0.05). Low VDR protein was an independent risk factor for poor prognosis (p < 0.05) and was negatively correlated with bone metastasis (p < 0.05). VDR protein and mRNA levels were both down-regulated in breast cancer with bone metastasis (both p < 0.05). The area under ROC curve (AUC) for VDR protein expression to identify patients with bone metastasis was 0.661 (p < 0.05) and the AUC for VDR level to predict 1-year 3-year, 5-year OS was 0.621, 0.664, and 0.805 in patients with bone metastasis, respectively (p < 0.05). VDR low expression accelerated bone metastasis and metastasis-related poor survival (both p < 0.05). Conclusion: VDR expression is a notably prognostic factor in primary breast cancer patients for predicting bone metastases and unfavorable clinical outcome.

Relevance of Breast Cancer Antiestrogen Resistance Genes in Human Breast Cancer Progression and Tamoxifen Resistance

2009 ◽  
Vol 27 (4) ◽  
pp. 542-549 ◽  
Author(s):  
Ton van Agthoven ◽  
Anieta M. Sieuwerts ◽  
Marion E. Meijer-van Gelder ◽  
Maxime P. Look ◽  
Marcel Smid ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Tamoxifen Resistance ◽  
Functional Screening ◽  
Mrna Levels ◽  
Antiestrogen Resistance ◽  
Tumor Aggressiveness ◽  
Breast Cancer Patients ◽  
Free Survival

Purpose We have previously identified a set of breast cancer antiestrogen resistance (BCAR) genes causing estrogen independence and tamoxifen resistance in vitro using a functional genetic screen. Here, we explored whether these BCAR genes provide predictive value for tamoxifen resistance and prognostic information for tumor aggressiveness in breast cancer patients. Patients and Methods mRNA levels of 10 BCAR genes (AKT1, AKT2, BCAR1, BCAR3, EGFR, ERBB2, GRB7, SRC, TLE3, and TRERF1) were measured in estrogen receptor–positive breast tumors using quantitative reverse-transcriptase polymerase chain reaction. Normalized mRNA levels were evaluated for association with progression-free survival (PFS) in 242 patients receiving tamoxifen as first-line monotherapy for recurrent disease, and with distant metastasis-free survival (MFS) in 413 lymph node-negative (LNN) primary breast cancer patients who did not receive systemic adjuvant therapy. Results Concerning tamoxifen resistance, BCAR3, ERBB2, GRB7, and TLE3 mRNA levels were predictive for PFS, independent of traditional predictive factors. By combining GRB7 (or ERBB2) and TLE3 mRNA levels, patients could be classified in three subgroups with distinct PFS. For the evaluation of tumor aggressiveness, AKT2, EGFR, and TRERF1 mRNA levels were all significantly associated with MFS, independent of traditional prognostic factors. Using the combined AKT2 and EGFR mRNA status, four prognostic groups were identified with different MFS outcomes. Conclusion The majority of BCAR genes, which were revealed to confer tamoxifen resistance and estrogen independence in vitro by functional screening, have clinical relevance, and associate with tamoxifen resistance and/or tumor aggressiveness in breast cancer patients.

scholarly journals Adherence to Newly Implemented Tamoxifen Therapy for Breast Cancer Patients in Rural Western Ethiopia

Breast Care ◽  
2021 ◽  
pp. 1-7
Author(s):  
Christian Felix Reibold ◽  
Wakuma Tariku ◽  
Pia Eber-Schulz ◽  
Sefonias Getachew ◽  
Adamu Addisie ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Health Care ◽  
Endocrine Therapy ◽  
Tamoxifen Therapy ◽  
Financial Hardship ◽  
Tamoxifen Treatment ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Rural Ethiopia ◽  
Western Ethiopia

<b><i>Introduction:</i></b> Endocrine therapy for breast cancer (BC) patients is highly underutilized in rural Ethiopia and other African countries. <b><i>Objective:</i></b> This study aims to assess the feasibility of and adherence to tamoxifen therapy in rural Ethiopia. <b><i>Methods:</i></b> We ascertained the hormone receptor (HR) status in 101 women diagnosed with BC from January 2010 to December 2015 and who had surgery in Aira Hospital, in rural Ethiopia. From 2013, tamoxifen was offered to patients with HR-positive (HR+) tumors. Prescription refill records and a structured questionnaire were used to assess receipt of and adherence to tamoxifen. <b><i>Results:</i></b> Of the 101 BC patients tested for HR status during the study period, 66 (65%) patients were HR+ and were eligible for tamoxifen treatment. However, 15 of the HR+ patients died before tamoxifen became available in 2013. Of the remaining 51 HR+ patients, 26 (51%) initiated tamoxifen but only 9 of them (35%) adhered to therapy (medication possession rate ≥80%, median observation 16.2 months). After 1 year, 52% of the patients were still adherent, and 9 patients had discontinued therapy. The reasons for non-initiation of tamoxifen included patient factors (<i>n</i> = 5), including financial hardship or lack of transportation, and health care provider factors (<i>n</i> = 12). <b><i>Conclusions:</i></b> Endocrine therapy for BC patients seems feasible in rural Western Ethiopia, although non-adherence due to financial hardship and a less developed health care infrastructure remains a major challenge. We postulate that the implementation of breast nurses could reduce patient and health system barriers and improve initiation of and adherence to endocrine treatment.

Clinical relevance of H-RAS, K-RAS and N-RAS in a large cohort of primary breast cancer patients

2018 ◽  
Author(s):  
M Banys-Paluchowski ◽  
K Milde-Langosch ◽  
T Fehm ◽  
I Witzel ◽  
L Oliveira-Ferrer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Clinical Relevance ◽  
Primary Breast Cancer ◽  
Large Cohort ◽  
Breast Cancer Patients
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