Low dose environmental radon exposure and breast tumor gene expression

Abstract

Background The International Agency for Research on Cancer classified radon and its decay-products as Group-1-human-carcinogens, and with the current knowledge they are linked specifically to lung cancer. Biokinetic models predict that radon could deliver a carcinogenic dose to breast tissue. Our previous work suggested that low-dose radon was associated with estrogen-receptor (ER)-negative breast cancer risk. However, there is limited research to examine the role of radon in breast cancer biology at the tissue level. We aim to understand molecular pathways linking radon exposure with breast cancer biology using transcriptome-wide-gene-expression from breast tumor and normal-adjacent tissues. Methods Our study included 943 women diagnosed with breast cancer from the Nurses’ Health Study (NHS) and NHSII. We estimated cumulative radon concentration for each participant up-to the year of breast cancer diagnosis by linking residential addresses with a radon exposure model. Transcriptome-wide-gene-expression was measured with the Affymetrix-Glue-Human-Transcriptome-Array-3.0 and Human-Transcriptome-Array-2.0. We performed covariate-adjusted linear-regression for individual genes and further employed pathway-analysis. All analyses were conducted separately for tumor and normal-adjacent samples and by ER-status. Results No individual gene was associated with cumulative radon exposure in ER-positive tumor, ER-negative tumor, or ER-negative normal-adjacent tissues at FDR < 5%. In ER-positive normal-adjacent samples, PLCH 2—reached transcriptome-wide-significance (FDR < 5%). Gene-set-enrichment-analyses identified 2-upregulated pathways (MAPK signaling and phosphocholine biosynthesis) enriched at FDR < 25% in ER-negative tumors and normal-adjacent tissues, and both pathways have been previously reported to play key roles in ionizing radiation induced tumorigenesis in experimental settings. Conclusion Our findings provide insights into the molecular pathways of radon exposure that may influence breast cancer etiology.

Proteomic and miRNA profiling of radon-induced skin damage in mice: FASN regulated by miRNAs

“…Additionally, cumulative radon exposure was associated with higher risk of ER negative breast cancer. The P38 MAPK signaling and phosphocholine synthesis gene sets were significantly enriched in ER negative breast tumor and ER negative normal-adjacent samples with higher cumulative radon exposure [ 3 ]. As the outermost organ of the human body, the skin suffers from environmental damage to agents such as air pollution and cigarette smoking.…”

“…Continuous radioactive decay of this gas emits high-energy alpha particles that may interact with biological tissues and macro-molecules. Similar to other ionizing radiation, radon and its decay products are mutagenic, as they could lead to single and double-strand DNA breaks, pyrimidine dimer formations, intra-and inter-chromosomal aberrations sister chromatid exchange micronuclei formation and eventually genomic instability [ 3 ]. It is indicated that alpha-particle exposure induces mainly unstable complex chromosome aberrations which do not contribute to radiation-associated cytogenetic risk [ 4 ].…”

“…Through many epidemiological studies regarding occupational exposure among miners and residential exposure among the general population, radon has been scientifically proven to cause lung cancer and radon exposure is the second most common cause of lung cancer after cigarette smoking [ 5–7 ]. Additionally, cumulative radon exposure was associated with higher risk of ER negative breast cancer [ 3 ]. However, biological effects after radon exposure in other organs have been rarely reported.…”

Residential radon exposure and cancer

“…39 In a follow-up study, it was found the MAPK signaling and phosphocholine biosynthesis pathways, which have roles in ionizing radiation-induced tumorigenesis, were enriched in estrogen receptor-negative and adjacentnormal samples at radon levels as low as 2 pCi, supporting biological plausibility of an association (False Discovery Rate <25%). 40 No significant associations were found in reported studies, and biological plausibility is only weakly supported, though two cohort studies suggest potential associations. More research is needed to investigate any potential association.…”

“… 39 In a follow-up study, it was found the MAPK signaling and phosphocholine biosynthesis pathways, which have roles in ionizing radiation-induced tumorigenesis, were enriched in estrogen receptor-negative and adjacentnormal samples at radon levels as low as 2 pCi, supporting biological plausibility of an association (False Discovery Rate <25%). 40 …”