Inorganic arsenic promotes luminal to basal transition and metastasis of breast cancer

Abstract

Inorganic arsenic (iAs/As 2 O 3 2−) is an environmental toxicant found in watersheds around the world including in densely populated areas. iAs is a class I carcinogen known to target the skin, lungs, bladder, and digestive organs, but its role as a primary breast carcinogen remains controversial. Here, we examined a different possibility: that exposure to iAs promotes the transition of well-differentiated epithelial breast cancer cells characterized by estrogen and progesterone receptor expression (ER+/ PR+), to more basal phenotypes characterized by active proliferation, and propensity to metastasis in vivo. Our results indicate two clear phenotypic responses to low-level iAs that depend on the duration of the exposure. Short-term pulses of iAs activate ER signaling, consistent with its reported pseudo-estrogen activity, but longer-term, chronic treatments for over 6 months suppresses both ER and PR expression and signaling. In fact, washout of these chronically exposed cells for up to 1 month failed to fully reverse the transcriptional and phenotypic effects of prolonged treatments, indicating durable changes in cellular physiologic identity. RNA-seq studies found that chronic iAs drives the transition toward more basal phenotypes characterized by impaired hormone receptor signaling despite the conservation of estrogen receptor expression. Because treatments for breast cancer patients are largely designed based on the detection of hormone receptor expression, our results suggest greater scrutiny of ER+ cancers in patients exposed to iAs, because these tumors may spawn more 2 | DANES Et Al. 2.3 | Proliferation assay MCF-7 and MCF-7 iAs300d cells were seeded at a density of 1000 cells/well of black-walled, 96 well plates (Greiner #655090) and left undisturbed for 24 hours. After 24 hours aggressive phenotypes than unexposed ER+ tumors, in particular, basal subtypes that tend to develop therapy resistance and metastasis.

Metabolomic dynamics of the arsenic-transformed bronchial epithelial cells and the derived cancer stem-like cells

“…Well-documented epidemiological and casecontrol studies in the United States, Bangladesh, Chile, China, Vietnam, Taiwan, India, and Mexico provided unequivocal evidence indicating association of increased cancer incidence rates with long-term arsenic exposure [3]. These observations were further supported by the facts of carcinogenic effects of arsenic during the development of cancers in lung [6], liver [7], skin [8], bladder [9], breast [10], prostate [11], kidney [12], etc., in a number of experimental settings [13].…”

Chronic Arsenic Exposure Upregulates the Expression of Basal Transcriptional Factors and Increases Invasiveness of the Non-Muscle Invasive Papillary Bladder Cancer Line RT4

“…Urothelial cancers take a long time to develop and currently it is not known if long-term exposure to arsenite (As 3+ ) could convert a papillary non-muscle invasive urothelial cancer to a more aggressive form that has the potential to metastasize and spread to distal organs. A recent study found that long-term exposure of the breast cancer cell line MCF-7 (luminal A sub-type) to As 3+ converts it to a more aggressive metastatic form with expression of basal markers [ 34 ]. This study supports the notion that As 3+ might play a similar role for the progression of papillary NMIUC luminal urothelial cancer to a more basal genotype and phenotype.…”

High Throughput Transcriptomics to Understand Chemical Drivers of Aggressive Breast Cancer Subtypes

“…Previous literature has shown that arsenic is capable of inducting transition from luminal to basal features, but this association has not been studied for the other chemicals. 57 One major limitation of the present study is that all exposures were done on an acute timescale (48 hours) while actual human exposures to the chemicals analyzed here are likely chronic, over the course of years or a lifetime. Another limitation is that only one cell type was used for this study, normal breast cells taken from a white woman.…”

“…Previous literature has shown that arsenic is capable of inducting transition from luminal to basal features, but this association has not been studied for the other chemicals. 57…”