Arsenic-induced cancer cell phenotype in human breast epithelia is estrogen receptor-independent but involves aromatase activation

Xu, Yuanyuan; Tokar, Erik J.; Waalkes, Michael P.

doi:10.1007/s00204-013-1131-4

Cited by 57 publications

(33 citation statements)

References 44 publications

(78 reference statements)

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“…In contrast, treatment of cells in culture usually involves a single, much shorter exposure to arsenic which often necessitates the use of higher than physiological concentrations to observe measurable effects. Chronic treatment of cells with low concentrations of arsenite can induce cellular transformation [89–92], global DNA hypomethylation [90–93], local DNA hypermethylation [93, 94], alterations in chromatin structure and splicing patterns [89], and increases in oncogenic gene expression [91, 95]. Recent research has indicated that chronic arsenic exposure alters methylation patterns of DNA repair factors involved in NER, leading to reduced RNA expression of ERCC1 and ERCC2 [96].…”

Section: Discussionmentioning

confidence: 99%

Inorganic arsenic inhibits the nucleotide excision repair pathway and reduces the expression of XPC

et al. 2017

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Chronic exposure to arsenic, most often through contaminated drinking water, has been linked to several types of cancer in humans, including skin and lung cancer. However, the mechanisms underlying its role in causing cancer are not well understood. There is evidence that exposure to arsenic can enhance the carcinogenicity of UV light in inducing skin cancers and may enhance the carcinogenicity of tobacco smoke in inducing lung cancers. The nucleotide excision repair (NER) pathway removes different types of DNA damage including those produced by UV light and components of tobacco smoke. The aim of the present study was to investigate the effect of sodium arsenite on the NER pathway in human lung fibroblasts (IMR-90 cells) and primary mouse keratinocytes. To measure NER, we employed a slot-blot assay to quantify the introduction and removal of UV light-induced 6-4 photoproducts (6-4 PP) and cyclobutane pyrimidine dimers (CPDs). We find a concentration-dependent inhibition of the removal of 6-4 PPs and CPDs in both cell types treated with arsenite. Treatment of both cell types with arsenite resulted in a significant reduction in the abundance of XPC, a protein that is critical for DNA damage recognition in NER. The abundance of RNA expressed from several key NER genes was also significantly reduced by treatment of IMR-90 cells with arsenite. Finally, treatment of IMR-90 cells with MG-132 abrogated the reduction in XPC protein, suggesting an involvement of the proteasome in the reduction of XPC protein produced by treatment of cells with arsenic. The inhibition of NER by arsenic may reflect one mechanism underlying the role of arsenic exposure in enhancing cigarette smoke-induced lung carcinogenesis and UV light-induced skin cancer, and it may provide some insights into the emergence of arsenic trioxide as a chemotherapeutic agent.

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Section: Discussionmentioning

confidence: 99%

Inorganic arsenic inhibits the nucleotide excision repair pathway and reduces the expression of XPC

et al. 2017

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“…Some in vitro and in vivo studies show cadmium and arsenic to mimic estrogen activity via the classic pathway mediated by ERs, 35-37 while more recent studies show that both arsenic and cadmium can induce basal-like cancer cell phenotypes in hormone-receptor-negative breast epithelial cell lines. 38,39 Additionally, evidence has supported mechanisms independent of ERs in estrogen-mediated breast cancer development through production of genotoxic estrogen metabolites (such as catechols and quinines), which can cause DNA damage and/or form DNA adducts. 34 These observations provide some biologic rationale to support the findings in the present study implicating exposure to arsenic or cadmium for risk of hormone-receptor-negative breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Residential Exposure to Estrogen Disrupting Hazardous Air Pollutants and Breast Cancer Risk

et al. 2015

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Background Some studies show increased breast cancer risk from exposure to xenoestrogens, but few have explored exposures via ambient air, which could impact large populations. Objectives This study explored the association between breast cancer risk and residential exposures to ambient estrogen disruptors among participants in a large cohort study, the California Teachers Study. Methods Participants consisted of 112,379 women free of breast cancer and living at a California address in 1995/1996. Eleven hazardous air pollutants (HAPs) from the U.S. EPA 2002 list were identified as estrogen disruptors based on published endocrine disrupting chemical lists and literature review. Census-tract estrogen disruptor concentrations modeled by the U.S. EPA in 2002 were assigned to participants’ baseline addresses. Cox proportional hazards models were used to estimate hazard ratios associated with exposure to each estrogen disruptor and a summary measure of nine estrogenic HAPs among all participants and selected subgroups, adjusting for age, race/birthplace, socioeconomic status, and known breast cancer risk factors. Results 5,361 invasive breast cancer cases were identified between 1995 and 2010. No associations were found between residential exposure to ambient estrogen disruptors and overall breast cancer risk or hormone-responsive-positive breast cancer risk, nor among targeted subgroups of participants (pre/peri-menopausal women, post-menopausal women, never smokers, non-movers, and never-smoking non-movers). However, elevated risks for hormone-responsive-negative tumors were observed for higher exposure to cadmium compounds and possibly inorganic arsenic among never-smoking non-movers. Conclusion Long-term low-dose exposure to ambient cadmium compounds or possibly inorganic arsenic may be a risk factor for breast cancer.

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“…CATLE cells also showed loss of expression of the tumor suppressor gene PTEN (Carracedo et al, 2011; Cooper et al, 2013), and the putative tumor suppressor gene SLC38A3 (Kholodnyuk et al, 2006), together with increased expression of the oncogene KRAS and increased expression of AKT1, a central member of a frequently activated signaling pathway in cancer (Carpten et al, 2007). Loss of PTEN expression and over-expression of KRAS are common in human lung cancer (Zhu et al, 2014; Kadara et al, 2012; Cooper et al 2013) and common in arsenic-induced malignant transformation of other cell types (Benbrahim-Tallaa et al, 2005; Tokar et al, 2010a; Ngalame et al, 2014a,b; Xu et al, 2014). ERK1/2 and p-ERK, which are critical to cell proliferation, are commonly activated in cancers and linked to RAS activation (e.g.…”

Section: Discussionmentioning

confidence: 99%

Chronic inorganic arsenic exposure in vitro induces a cancer cell phenotype in human peripheral lung epithelial cells

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Ngalame

Makia

et al. 2015

Toxicology and Applied Pharmacology

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Inorganic arsenic is a human lung carcinogen. We studied the ability of chronic inorganic arsenic (2 μM; as sodium arsenite) exposure to induce a cancer phenotype in the immortalized, non-tumorigenic human lung peripheral epithelial cell line, HPL-1D. After 38 weeks of continuous arsenic exposure, secreted matrix metalloproteinase-2 (MMP2) activity increased to over 200% of control, levels linked to arsenic-induced cancer phenotypes in other cell lines. The invasive capacity of these chronic arsenic-treated lung epithelial (CATLE) cells increased to 320% of control and colony formation increased to 280% of control. CATLE cells showed enhanced proliferation in serum-free media indicative of autonomous growth. Compared to control cells, CATLE cells showed reduced protein expression of the tumor suppressor gene PTEN (decreased to 26% of control) and the putative tumor suppressor gene SLC38A3 (14% of control). Morphological evidence of epithelial-to-mesenchymal transition (EMT) occurred in CATLE cells together with appropriate changes in expression of the EMT markers vimentin (VIM; increased to 300% of control) and e-cadherin (CDH1; decreased to 16% of control). EMT is common in carcinogenic transformation of epithelial cells. CATLE cells showed increased KRAS (291%), ERK1/2 (274%), phosphorylated ERK (p-ERK; 152%), and phosphorylated AKT1 (p-AKT1; 170%) protein expression. Increased transcript expression of metallothioneins, MT1A and MT2A and the stress response genes HMOX1 (690%) and HIF1A (247%) occurred in CATLE cells possibly in adaptation to chronic arsenic exposure. Thus, arsenic induced multiple cancer cell characteristics in human peripheral lung epithelial cells. This model may be useful to assess mechanisms of arsenic-induced lung cancer.

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Arsenic-induced cancer cell phenotype in human breast epithelia is estrogen receptor-independent but involves aromatase activation

Cited by 57 publications

References 44 publications

Inorganic arsenic inhibits the nucleotide excision repair pathway and reduces the expression of XPC

Inorganic arsenic inhibits the nucleotide excision repair pathway and reduces the expression of XPC

Residential Exposure to Estrogen Disrupting Hazardous Air Pollutants and Breast Cancer Risk

Chronic inorganic arsenic exposure in vitro induces a cancer cell phenotype in human peripheral lung epithelial cells

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