Tumor expression of environmental chemical-responsive genes and breast cancer mortality

in Endocrine-Related Cancer
Authors:
Vasily N Aushev Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA

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Kalpana Gopalakrishnan Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA

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Susan L Teitelbaum Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA

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Humberto Parada Jr Division of Epidemiology & Biostatistics, School of Public Health, San Diego State University, San Diego, California, USA

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Regina M Santella Department of Environmental Health Sciences, Columbia University, New York, New York, USA

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Marilie D Gammon University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

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Jia Chen Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA

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Correspondence should be addressed to J Chen: jia.chen@mssm.edu
DOI:
https://doi.org/10.1530/ERC-19-0357
Volume/Issue:
Volume 26: Issue 12
Article Type:
Research Article
Page Range:
843–851
Online Publication Date:
Dec 2019
Copyright:
© 2019 Society for Endocrinology 2019
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Environmental phenols and phthalates are common ingredients in personal care products and some have been implicated in breast cancer progression. We have previously identified genes differentially expressed in response to low-dose exposure to diethyl phthalate (DEP) and methyl paraben (MPB) in a rat model. Herein we explore if these genes are associated with breast cancer mortality in humans. We profiled MPB- and DEP-responsive genes in tumors by NanoString® from a population-based cohort of 606 women with first primary breast cancer among whom 119 breast cancer-specific deaths occurred within 15+ years of follow-up. For each gene, Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results were validated in two publicly available datasets. The following results were obtained. From 107 DEP- and 77 MPB-responsive genes profiled, 44 and 30 genes, respectively, were significantly associated with breast cancer-specific mortality. Some top DEP-responsive genes are novel for breast cancer mortality, such as ABHD14B (for high-vs-low expression, HR 0.36, 95% CI: 0.2–0.5) and TMC4 (HR 0.37, 95% CI: 0.3–0.5); top hits for MPB (SLC40A1 (HR 0.37, 95% CI: 0.3–0.5) and NTN4 (HR 0.39, 95% CI: 0.3–0.6)) are well-known predictors of breast cancer survival. PLEKHA6 was another novel survival predictor, sensitive to hormonal receptor status (HR 0.5, 95% CI 0.3–0.9 for hormonal receptor-positive and HR 3.2, 95% CI 1.7–6.2 for -negative group). In conclusion, tumor expression of DEP- and MPB-responsive genes is associated with breast cancer mortality, supporting that exposure to these chemicals may influence the progression of breast cancer.

Supplementary Materials

    • Figure S1. Validation of top associated genes in independent datasets
    • Figure S2. Survival-associated genes after stratification by the PAM50-defined risk-of-recurrence.
    • Table S1. MPB-responsive genes and their association with breast cancer mortality.
    • Table S2. DEP-responsive genes and their association with breast cancer mortality.
    • Table S3. Breast cancer mortality association of MPB- and DEP-responsive genes after stratification by ER/PR status and molecular subtypes
    • Table S4. Breast cancer mortality association of MPB- and DEP-responsive genes within METABRIC dataset

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Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© 2019 Society for Endocrinology 2019
Page(s):
9
Received Date:
05 Sep 2019
Accepted Date:
07 Oct 2019
Print Publication Date:
01 Dec 2019
Online Publication Date:
Dec 2019
Keywords:
breast; oncology; mammary gland; estrogen receptor

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