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Association of H3K9me3 and H3K27me3 repressive histone marks with breast cancer subtypes in the Nurses’ Health Study

  • Epidemiology
  • Published:
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Abstract

Repressive histone tail modifications have been associated with molecular breast cancer subtypes. We investigated whether histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) were associated with tumor features and subtypes while adjusting for prospectively collected reproductive and lifestyle breast cancer risk factors. We have tissue microarray data with immunohistochemical marker information on 804 incident cases of invasive breast cancer diagnosed from 1976–2000 in the Nurses’ Health Study. Tissue microarray sections were stained for global H3K9me3 and H3K27me3, and scored into four categories. Multivariate odds ratios (OR) and 95 % confidence intervals (CI) were calculated using logistic regression models for tumor features and subtypes, adjusting for breast cancer risk factors. While there were no significant associations between H3K9me3 and tumor features, H3K27me3 was significantly associated with lower grade tumors compared to high grade tumors in the multivariate model (OR = 1.95, 95 % CI 1.35–2.81, p = 0.0004). H3K27me3 was suggestively associated with estrogen receptor-positive (ER+) tumors (OR = 1.47, 95 % CI 0.97–2.23, p = 0.07). In subtype analyses, H3K27me3 was positively associated with the luminal A subtype compared to all other subtypes (OR = 1.42, 95 % CI 1.14–1.77, p = 0.002), and was inversely associated with HER2-type (OR = 0.58, 95 % CI 0.37–0.91, p = 0.02) and basal-like breast cancer (OR = 0.52, 95 % CI 0.36–0.76, p = 0.0006). In the largest immunohistochemical examination of H3K9me3 and H3K27me3 in breast cancer, we found that H3K27me3 positivity, but not H3K9me3, was associated with lower grade tumors and the luminal A subtype after adjusting for reproductive and lifestyle breast cancer risk factors.

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Abbreviations

BMI:

Body mass index

BRCA1:

Breast cancer 1

ChIP:

Chromatin immunoprecipitation

CI:

Confidence interval

CK5/6:

Cytokeratin 5/6

DAB:

Diaminobenzidine

EGFR:

Epidermal growth factor receptor

EZH2:

Enhancer of zeste homolog 2

ER:

Estrogen receptor

FFPE:

Formalin-fixed paraffin-embedded

H3:

Histone 3

H3K9me3:

Histone 3 lysine 9 trimethylation

H3K27me3:

Histone 3 lysine 27 trimethylation

HER2:

Human epidermal growth factor receptor 2

NHS:

Nurses’ Health Study

IHC:

Immunohistochemistry

OR:

Odds ratio

PMH:

Post-menopausal hormone

PR:

Progesterone receptor

PRC2:

Polycomb repressive complex 2

SNP:

Single nucleotide polymorphism

TMA:

Tissue microarray

TNBC:

Triple-negative breast cancer

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Acknowledgements

This study was supported by the Harvard/National Cancer Institute SPORE in Breast Cancer Career Development Award (1999P011116). MAH was supported by the National Institutes of Health Cancer Epidemiology Training Grant (NIH T32 CA09001). We would like to thank the participants and staff of the Nurses’ Health Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD,MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. The authors assume full responsibility for analyses and interpretation of these data.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Standards

All data collection was conducted with approval of appropriate institutional review boards to protect human subjects with consent and data protection systems in place. Data analysis for this manuscript was conducted on de-identified data sets.

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Authors and Affiliations

  1. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Megan A. Healey, Rong Hu, Rulla M. Tamimi & Aditi Hazra

  2. Department of Epidemiology, Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA, USA

    Megan A. Healey, Rulla M. Tamimi & Aditi Hazra

  3. Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    Andrew H. Beck, Laura C. Collins & Stuart J. Schnitt

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  1. Megan A. Healey
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Healey, M.A., Hu, R., Beck, A.H. et al. Association of H3K9me3 and H3K27me3 repressive histone marks with breast cancer subtypes in the Nurses’ Health Study. Breast Cancer Res Treat 147, 639–651 (2014). https://doi.org/10.1007/s10549-014-3089-1

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