Identification and targeting of selective vulnerability rendered by tamoxifen resistance
Abstract Background The estrogen receptor (ER)-positive breast cancer represents over 80% of all breast cancer cases. Even though adjuvant hormone therapy with tamoxifen (TMX) is saving lives of patients with ER-positive breast cancer, the acquired resistance to TMX anti-estrogen therapy is the main...
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doaj-f5121b8f3c484ea1840e8f42cfd9a4072021-04-02T09:23:54ZengBMCBreast Cancer Research1465-542X2020-07-0122111610.1186/s13058-020-01315-5Identification and targeting of selective vulnerability rendered by tamoxifen resistanceMadhurendra Singh0Xiaolei Zhou1Xinsong Chen2Gema Sanz Santos3Sylvain Peuget4Qing Cheng5Ali Rihani6Elias S. J. Arnér7Johan Hartman8Galina Selivanova9Department of Microbiology, Tumor and Cell Biology, Karolinska InstitutetDepartment of Microbiology, Tumor and Cell Biology, Karolinska InstitutetDepartment of Oncology and Pathology, Karolinska Institutet, CCKDepartment of Microbiology, Tumor and Cell Biology, Karolinska InstitutetDepartment of Microbiology, Tumor and Cell Biology, Karolinska InstitutetDivision of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Microbiology, Tumor and Cell Biology, Karolinska InstitutetDivision of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Oncology and Pathology, Karolinska Institutet, CCKDepartment of Microbiology, Tumor and Cell Biology, Karolinska InstitutetAbstract Background The estrogen receptor (ER)-positive breast cancer represents over 80% of all breast cancer cases. Even though adjuvant hormone therapy with tamoxifen (TMX) is saving lives of patients with ER-positive breast cancer, the acquired resistance to TMX anti-estrogen therapy is the main hurdle for successful TMX therapy. Here we address the mechanism for TMX resistance and explore the ways to eradicate TMX-resistant breast cancer in both in vitro and ex vivo experiments. Experimental design To identify compounds able to overcome TMX resistance, we used short-term and long-term viability assays in cancer cells in vitro and in patient samples in 3D ex vivo, analysis of gene expression profiles and cell line pharmacology database, shRNA screen, CRISPR-Cas9 genome editing, real-time PCR, immunofluorescent analysis, western blot, measurement of oxidative stress using flow cytometry, and thioredoxin reductase 1 enzymatic activity. Results Here, for the first time, we provide an ample evidence that a high level of the detoxifying enzyme SULT1A1 confers resistance to TMX therapy in both in vitro and ex vivo models and correlates with TMX resistance in metastatic samples in relapsed patients. Based on the data from different approaches, we identified three anticancer compounds, RITA (Reactivation of p53 and Induction of Tumor cell Apoptosis), aminoflavone (AF), and oncrasin-1 (ONC-1), whose tumor cell inhibition activity is dependent on SULT1A1. We discovered thioredoxin reductase 1 (TrxR1, encoded by TXNRD1) as a target of bio-activated RITA, AF, and ONC-1. SULT1A1 depletion prevented the inhibition of TrxR1, induction of oxidative stress, DNA damage signaling, and apoptosis triggered by the compounds. Notably, RITA efficiently suppressed TMX-unresponsive patient-derived breast cancer cells ex vivo. Conclusion We have identified a mechanism of resistance to TMX via hyperactivated SULT1A1, which renders selective vulnerability to anticancer compounds RITA, AF, and ONC-1, and provide a rationale for a new combination therapy to overcome TMX resistance in breast cancer patients. Our novel findings may provide a strategy to circumvent TMX resistance and suggest that this approach could be developed further for the benefit of relapsed breast cancer patients.http://link.springer.com/article/10.1186/s13058-020-01315-5Tamoxifen resistanceSULT1A1RITAAminoflavoneOncrasin-1TrxR1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Madhurendra Singh Xiaolei Zhou Xinsong Chen Gema Sanz Santos Sylvain Peuget Qing Cheng Ali Rihani Elias S. J. Arnér Johan Hartman Galina Selivanova |
spellingShingle |
Madhurendra Singh Xiaolei Zhou Xinsong Chen Gema Sanz Santos Sylvain Peuget Qing Cheng Ali Rihani Elias S. J. Arnér Johan Hartman Galina Selivanova Identification and targeting of selective vulnerability rendered by tamoxifen resistance Breast Cancer Research Tamoxifen resistance SULT1A1 RITA Aminoflavone Oncrasin-1 TrxR1 |
author_facet |
Madhurendra Singh Xiaolei Zhou Xinsong Chen Gema Sanz Santos Sylvain Peuget Qing Cheng Ali Rihani Elias S. J. Arnér Johan Hartman Galina Selivanova |
author_sort |
Madhurendra Singh |
title |
Identification and targeting of selective vulnerability rendered by tamoxifen resistance |
title_short |
Identification and targeting of selective vulnerability rendered by tamoxifen resistance |
title_full |
Identification and targeting of selective vulnerability rendered by tamoxifen resistance |
title_fullStr |
Identification and targeting of selective vulnerability rendered by tamoxifen resistance |
title_full_unstemmed |
Identification and targeting of selective vulnerability rendered by tamoxifen resistance |
title_sort |
identification and targeting of selective vulnerability rendered by tamoxifen resistance |
publisher |
BMC |
series |
Breast Cancer Research |
issn |
1465-542X |
publishDate |
2020-07-01 |
description |
Abstract Background The estrogen receptor (ER)-positive breast cancer represents over 80% of all breast cancer cases. Even though adjuvant hormone therapy with tamoxifen (TMX) is saving lives of patients with ER-positive breast cancer, the acquired resistance to TMX anti-estrogen therapy is the main hurdle for successful TMX therapy. Here we address the mechanism for TMX resistance and explore the ways to eradicate TMX-resistant breast cancer in both in vitro and ex vivo experiments. Experimental design To identify compounds able to overcome TMX resistance, we used short-term and long-term viability assays in cancer cells in vitro and in patient samples in 3D ex vivo, analysis of gene expression profiles and cell line pharmacology database, shRNA screen, CRISPR-Cas9 genome editing, real-time PCR, immunofluorescent analysis, western blot, measurement of oxidative stress using flow cytometry, and thioredoxin reductase 1 enzymatic activity. Results Here, for the first time, we provide an ample evidence that a high level of the detoxifying enzyme SULT1A1 confers resistance to TMX therapy in both in vitro and ex vivo models and correlates with TMX resistance in metastatic samples in relapsed patients. Based on the data from different approaches, we identified three anticancer compounds, RITA (Reactivation of p53 and Induction of Tumor cell Apoptosis), aminoflavone (AF), and oncrasin-1 (ONC-1), whose tumor cell inhibition activity is dependent on SULT1A1. We discovered thioredoxin reductase 1 (TrxR1, encoded by TXNRD1) as a target of bio-activated RITA, AF, and ONC-1. SULT1A1 depletion prevented the inhibition of TrxR1, induction of oxidative stress, DNA damage signaling, and apoptosis triggered by the compounds. Notably, RITA efficiently suppressed TMX-unresponsive patient-derived breast cancer cells ex vivo. Conclusion We have identified a mechanism of resistance to TMX via hyperactivated SULT1A1, which renders selective vulnerability to anticancer compounds RITA, AF, and ONC-1, and provide a rationale for a new combination therapy to overcome TMX resistance in breast cancer patients. Our novel findings may provide a strategy to circumvent TMX resistance and suggest that this approach could be developed further for the benefit of relapsed breast cancer patients. |
topic |
Tamoxifen resistance SULT1A1 RITA Aminoflavone Oncrasin-1 TrxR1 |
url |
http://link.springer.com/article/10.1186/s13058-020-01315-5 |
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