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

  • Inorganic Compounds
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Abstract

Accumulating data suggest arsenic may be an endocrine disruptor and tentatively linked to breast cancer by some studies. Therefore, we tested the effects of chronic inorganic arsenic exposure on the normal estrogen receptor (ER)-negative breast epithelial cell line, MCF-10A. Cells were chronically exposed to a low-level arsenite (500 nM) for up to 24 weeks. Markers of cancer cell phenotype and the expression of critical genes relevant to breast cancer or stem cells (SCs) were examined. After 24 weeks, chronic arsenic-exposed breast epithelial (CABE) cells showed increases in secreted MMP activity, colony formation, invasion, and proliferation rate, indicating an acquired cancer cell phenotype. These CABE cells presented with basal-like breast cancer characteristics, including ER-α, HER-2, and progesterone receptor negativity, and overexpression of K5 and p63. Putative CD44+/CD24−/low breast SCs were increased to 80 % over control in CABE cells. CABE cells also formed multilayer cell mounds, indicative of loss of contact inhibition. These mounds showed high levels of K5 and p63, indicating the potential presence of cancer stem cells (CSCs). Epithelial-to-mesenchymal transition occurred during arsenic exposure. Overexpression of aromatase, a key rate-limiting enzyme in estrogen synthesis, occurred with arsenic starting early on in exposure. Levels of 17β-estradiol increased in CABE cells and their conditioned medium. The aromatase inhibitor letrozole abolished arsenic-induced increases in 17β-estradiol production and reversed cancer cell phenotype. Thus, chronic arsenic exposure drives human breast epithelia into a cancer cell phenotype with an apparent overabundance of putative CSCs. Arsenic appears to transform breast epithelia through overexpression of aromatase, thereby activating oncogenic processes independent of ER.

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This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH); however, the statements, opinions, or conclusions contained therein do not necessarily represent the statements, opinions, or conclusions of NIEHS, NIH, or the US government.

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  1. National Toxicology Program Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

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

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  1. Yuanyuan Xu
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  2. Erik J. Tokar
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  3. Michael P. Waalkes
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Correspondence to Michael P. Waalkes.

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Xu, Y., Tokar, E.J. & Waalkes, M.P. Arsenic-induced cancer cell phenotype in human breast epithelia is estrogen receptor-independent but involves aromatase activation. Arch Toxicol 88, 263–274 (2014). https://doi.org/10.1007/s00204-013-1131-4

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