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

in Endocrine-Related Cancer
Correspondence should be addressed to J Chen: jia.chen@mssm.edu
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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.

Downloadable 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

 

      Society for Endocrinology

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    Correlation of expression of 77 MPB-related genes with long-term breast cancer-specific survival of LIBCSP patients. (A) Volcano plot, showing age- and stage-adjusted Cox models, with each dot corresponding to a gene, horizontal axis displaying hazard ratio of high expression group comparing to low expression group (i.e. for the genes on the left higher expression is associated with better survival, genes on the right are associated with worse survival) and vertical axis displaying logarithm of P value of the given Cox model. (B) Survival curves for representative genes associated with longer (SLC40A1, NTN4) and shorter (CHEK1, MCM2) survival. A full colour version of this figure is available at https://doi.org/10.1530/ERC-19-0357.

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    Correlation of expression of 107 DEP-related genes with breast cancer-specific survival; for legend see Fig. 1. A full colour version of this figure is available at https://doi.org/10.1530/ERC-19-0357.

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    Survival-associated genes specific for hormonal receptor (ER/PR) expression status. Four representative genes shown, data for all genes are in the Supplementary Table 3. A full colour version of this figure is available at https://doi.org/10.1530/ERC-19-0357.

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