Arsenic trioxide re-sensitizes ERα-negative breast cancer cells to endocrine therapy by restoring ERα expression in vitro and in vivo

Zhang, Weijie; Wang, Liuxing; Fan, Qingxia; Wu, Xin-ai; Wang, Feng; Wang, Rui; Ma, Zhuo; Yang, Jianhua; Lu, Shih Hsin

doi:10.3892/or.2011.1352

Cited by 6 publications

(3 citation statements)

References 23 publications

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“…Arsenic was also active in the steroid synthesis and estrogenic activity assays, which could indicate that a ) other biological activity of arsenic limits its activity in the mammary gland, such as the differential induction of cell death in breast cancer cells ( Ruiz-Ramos et al 2009 ), or b ) further epidemiologic study might detect an association between arsenic and breast cancer. Interestingly, arsenic has been investigated as a clinical treatment for advanced breast cancer ( Liu et al 2012 ; Zhang et al 2011 ), and a negative association has recently been observed between exposure to elevated arsenic levels in drinking water and breast cancer mortality in Chile ( Smith et al 2014 ). Caprolactam emerged from the pilot test without any indications of genotoxicity, but there is no human evidence, and scant data on endocrine disruption or cancer hallmarks.…”

Section: Resultsmentioning

confidence: 99%

Screening for Chemical Contributions to Breast Cancer Risk: A Case Study for Chemical Safety Evaluation

Schwarzman

Ackerman

Dairkee

et al. 2015

Environ Health Perspect

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BackgroundCurrent approaches to chemical screening, prioritization, and assessment are being reenvisioned, driven by innovations in chemical safety testing, new chemical regulations, and demand for information on human and environmental impacts of chemicals. To conceptualize these changes through the lens of a prevalent disease, the Breast Cancer and Chemicals Policy project convened an interdisciplinary expert panel to investigate methods for identifying chemicals that may increase breast cancer risk.MethodsBased on a review of current evidence, the panel identified key biological processes whose perturbation may alter breast cancer risk. We identified corresponding assays to develop the Hazard Identification Approach for Breast Carcinogens (HIA-BC), a method for detecting chemicals that may raise breast cancer risk. Finally, we conducted a literature-based pilot test of the HIA-BC.ResultsThe HIA-BC identifies assays capable of detecting alterations to biological processes relevant to breast cancer, including cellular and molecular events, tissue changes, and factors that alter susceptibility. In the pilot test of the HIA-BC, chemicals associated with breast cancer all demonstrated genotoxic or endocrine activity, but not necessarily both. Significant data gaps persist.ConclusionsThis approach could inform the development of toxicity testing that targets mechanisms relevant to breast cancer, providing a basis for identifying safer chemicals. The study identified important end points not currently evaluated by federal testing programs, including altered mammary gland development, Her2 activation, progesterone receptor activity, prolactin effects, and aspects of estrogen receptor β activity. This approach could be extended to identify the biological processes and screening methods relevant for other common diseases.CitationSchwarzman MR, Ackerman JM, Dairkee SH, Fenton SE, Johnson D, Navarro KM, Osborne G, Rudel RA, Solomon GM, Zeise L, Janssen S. 2015. Screening for chemical contributions to breast cancer risk: a case study for chemical safety evaluation. Environ Health Perspect 123:1255–1264; http://dx.doi.org/10.1289/ehp.1408337

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Section: Resultsmentioning

confidence: 99%

Screening for Chemical Contributions to Breast Cancer Risk: A Case Study for Chemical Safety Evaluation

Schwarzman

Ackerman

Dairkee

et al. 2015

Environ Health Perspect

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“…Arsenic trioxide could suppress cancers of the liver, prostate, and esophagus through demethylation or, for example, by induction of apoptosis. Zhang et al recently showed that arsenic trioxide induces re-expression of ER in MDA-MB-435s and also inhibits tumour growth in mice [22]. However, there is evidence that MDA-MB-435 cell line is not actually from a breast cancer lineage, but in fact are derived from a melanoma cell line, M14 [23].…”

Section: Discussionmentioning

confidence: 99%

Arsenic Induces Functional Re-Expression of Estrogen Receptor α by Demethylation of DNA in Estrogen Receptor-Negative Human Breast Cancer

Zhou

Liu

et al. 2012

PLoS ONE

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Estrogen receptor α (ERα) is a marker predictive for response of breast cancers to endocrine therapy. About 30% of breast cancers, however, are hormone- independent because of lack of ERα expression. New strategies are needed for re-expression of ERα and sensitization of ER-negative breast cancer cells to selective ER modulators. The present report shows that arsenic trioxide induces reactivated ERα, providing a target for therapy with ER antagonists. Exposure of ER-negative breast cancer cells to arsenic trioxide leads to re-expression of ERα mRNA and functional ERα protein in in vitro and in vivo. Luciferase reporter gene assays and 3-(4,5-dimethylthiazol-2-yl)- 5-(3-carboxymethoxyphenyl)- 2-(4-sulfophenyl)- 2H-tetrazolium (MTS) assays show that, upon exposure to arsenic trioxide, formerly unresponsive, ER-negative MDA-MB-231 breast cancer cells become responsive to ER antagonists, 4-hydroxytamoxifen and ICI 182,780. Furthermore, methylation- specific PCR and bisulfite-sequencing PCR assays show that arsenic trioxide induces partial demethylation of the ERα promoter. A methyl donor, S-adenosylmethionine (SAM), reduces the degree of arsenic trioxide-induced re-expression of ERα and demethylation. Moreover, Western blot and ChIP assays show that arsenic trioxide represses expression of DNMT1 and DNMT3a along with partial dissociation of DNMT1 from the ERα promoter. Thus, arsenic trioxide exhibits a previously undefined function which induces re-expression ERα in ER-negative breast cancer cells through demethylation of the ERα promoter. These findings could provide important information regarding the application of therapeutic agents targeting epigenetic changes in breast cancers and potential implication of arsenic trioxide as a new drug for the treatment of ER–negative human breast cancer.

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“…In contrast to irreversible genetic mutations, epigenetic changes such as occur in the ERα gene are potentially reversible (34) making these changes amenable to pharmacological interventions (35). Currently there are no agents that achieve re-expression of ERα in the clinic although certain HDAC inhibitors, demethylating agents, epigallocatechin-3-gallate (a major polyphenol in green tea) and arsenic trioxide have been shown to re-express ERα in experimental models (36,37). Src expression and activity is inversely correlated with ERα levels in human primary breast cancers (15,38,39) suggesting that Src kinase inhibition may be a strategy for re-expression of ERα and restoration of sensitivity to endocrine therapies.…”

Section: Discussionmentioning

confidence: 99%

Dual Src Kinase/Pretubulin Inhibitor KX-01, Sensitizes ERα-negative Breast Cancers to Tamoxifen through ERα Reexpression

Anbalagan

Sheng

Fleischer

et al. 2017

Molecular Cancer Research

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Unlike breast cancer that is positive for estrogen receptor-α (ERα), there are no targeted therapies for triple negative breast cancer (TNBC). ERα is silenced in TNBC through epigenetic changes including DNA methylation and histone acetylation. Restoring ERα expression in TNBC may sensitize patients to endocrine therapy. Expression of c-Src and ERα are inversely correlated in breast cancer suggesting that c-Src inhibition may lead to re-expression of ERα in TNBC. KX-01 is a peptide substrate-targeted Src/pretubulin inhibitor in clinical trials for solid tumors. KX-01 (1 mg/kg body weight-BID) inhibited growth of tamoxifen-resistant MDA-MB-231 and MDA-MB-157 TNBC xenografts in NUDE mice that was correlated with Src kinase inhibition. KX-01 also increased ERα mRNA and protein, as well as increased the ERα targets progesterone receptor (PR), pS2 (TFF1), cyclin D1 (CCND1) and c-myc (MYC) in MDA-MB-231 and MDA-MB-468 but not MDA-MB-157 xenografts. MDA-MB-231 and MDA-MB-468 tumors exhibited reduction in mesenchymal markers (vimentin, β-catenin) and increase in epithelial marker (E-cadherin) suggesting mesenchymal-to-epithelial transition (MET). KX-01 sensitized MDA-MB-231 and MDA-MB-468 tumors to tamoxifen growth inhibition and tamoxifen repression of the ERα targets pS2, cyclin D1 and c-myc. Chromatin immunoprecipitation (ChIP) of the ERα promoter in KX-01 treated tumors demonstrated enrichment of active transcription marks (acetyl-H3, acetyl-H3Lys9), dissociation of HDAC1, and recruitment of RNA polymerase II. Methylation-specific PCR and bisulfite sequencing demonstrated no alteration in ERα promoter methylation by KX-01. These data demonstrate that in addition to Src kinase inhibition, peptidomimetic KX-01 restores ERα expression in TNBC through changes in histone acetylation that sensitize tumors to tamoxifen. Implications: Src kinase/pretubulin inhibitor KX-01 restores functional ERα expression in ERα- breast tumors, a novel treatment strategy to treat triple-negative breast cancer.

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Arsenic trioxide re-sensitizes ERα-negative breast cancer cells to endocrine therapy by restoring ERα expression in vitro and in vivo

Cited by 6 publications

References 23 publications

Screening for Chemical Contributions to Breast Cancer Risk: A Case Study for Chemical Safety Evaluation

Screening for Chemical Contributions to Breast Cancer Risk: A Case Study for Chemical Safety Evaluation

Arsenic Induces Functional Re-Expression of Estrogen Receptor α by Demethylation of DNA in Estrogen Receptor-Negative Human Breast Cancer

Dual Src Kinase/Pretubulin Inhibitor KX-01, Sensitizes ERα-negative Breast Cancers to Tamoxifen through ERα Reexpression

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