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Associations between genetic variants in the TGF-β signaling pathway and breast cancer risk among Hispanic and non-Hispanic white women

  • Epidemiology
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Abstract

The TGF-β signaling pathway has a significant role in breast cancer initiation and promotion by regulating various cellular processes. We evaluated whether genetic variation in eight genes (TGF-β1, TGF-β2, TGF-βR1, TGF-βR2, TGF-βR3, RUNX1, RUNX2, and RUNX3) is associated with breast cancer risk in women from the Breast Cancer Health Disparities Study. A total of 3,524 cases (1,431 non-Hispanic whites (NHW); 2,093 Hispanics/Native Americans(NA)) and 4,209 population-based controls (1,599 NHWs; 2,610 Hispanics/NAs) were included in analyses. Genotypes for 47 single nucleotide polymorphisms (SNPs) were determined. Additionally, 104 ancestral informative markers estimated proportion of NA ancestry. Associations with breast cancer risk overall, by menopausal status, NA ancestry, and estrogen receptor (ER)/progesterone receptor tumor phenotype were evaluated. After adjustment for multiple comparisons, two SNPs were significantly associated with breast cancer risk: RUNX3 (rs906296 ORCG/GG = 1.15 95 % CI 1.04–1.26) and TGF-β1 (rs4803455 ORCA/AA = 0.89 95 % CI 0.81–0.98). RUNX3 (rs906296) and TGF-βR2 (rs3773644) were associated with risk in pre-menopausal women (p adj = 0.002 and 0.02, respectively) and in those with intermediate to high NA ancestry (p adj = 0.04 and 0.01, respectively). Self-reported race was strongly correlated with NA ancestry (r = 0.86). There was a significant interaction between NA ancestry and RUNX1 (rs7279383, p adj = 0.04). Four RUNX SNPs were associated with increased risk of ER− tumors. Results provide evidence that genetic variation in TGF-β and RUNX genes are associated with breast cancer risk. This is the first report of significant associations between genetic variants in TGF-β and RUNX genes and breast cancer risk among women of NA ancestry.

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Acknowledgments

This research was funded in part through a Susan G. Komen training grant: Breast Cancer Disparities Epidemiology Research Training Program (KG090926) to Dr. K. Baumgartner and Dr. R. Baumgartner at the University of Louisville. The Breast Cancer Health Disparities Study was funded by Grant CA14002 from the National Cancer Institute to Dr. Slattery. The San Francisco Bay Area Breast Cancer Study was supported by Grants CA63446 and CA77305 from the National Cancer Institute, Grant DAMD17-96-1-6071 from the U.S. Department of Defense and Grant 7 PB-0068 from the California Breast Cancer Research Program. The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute’s Surveillance, Epidemiology and End Results Program under contract HHSN261201000036C awarded to the Cancer Prevention Institute of California; and the Centers for Disease Control and Prevention’s National Program of Cancer Registries, under agreement #1U58 DP000807-01 awarded to the Public Health Institute. The 4-Corner’s Breast Cancer Study was funded by Grants CA078682, CA078762, CA078552, and CA078802 from the National Cancer Institute. The research also was supported by the Utah Cancer Registry, which is funded by contract N01-PC-67000 from the National Cancer Institute, with additional support from the State of Utah Department of Health, the New Mexico Tumor Registry, and the Arizona and Colorado cancer registries, funded by the Centers for Disease Control and Prevention National Program of Cancer Registries and additional state support. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official view of the National Cancer Institute or endorsement by the State of California Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors. The Mexico Breast Cancer Study was funded by Consejo Nacional de Ciencia y Tecnología (CONACyT) (SALUD-2002-C01-7462). We would also like to acknowledge the contributions of the following individuals to the study: Sandra Edwards for data harmonization oversight; Erica Wolff and Michael Hoffman for laboratory support; Carolyn Ortega for her assistance with data management for the Mexico Breast Cancer Study, Jocelyn Koo for data management for the San Francisco Bay Area Breast Cancer Study, Dr. Tim Byers for his contribution to the 4-Corner’s Breast Cancer Study, and Dr. Josh Galanter for assistance in selection of AIMS markers for the study.

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Authors and Affiliations

  1. Department of Epidemiology and Population Health, School of Public Health and Information Sciences, James Graham Brown Cancer Center, University of Louisville, 485 E. Gray St. Room, Louisville, KY, 40202, USA

    Stephanie D. Boone, Kathy B. Baumgartner, Richard N. Baumgartner, Avonne E. Connor, Christina M. Pinkston, Frank D. Groves & Richard A. Kerber

  2. Cancer Prevention Institute of California, Fremont, CA, 94538, USA

    Esther M. John

  3. Division of Epidemiology, Department of Health Research and Policy, and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Esther M. John

  4. Department of Biology, University of Colorado, Colorado Springs, CO, 80045, USA

    Lisa M. Hines

  5. Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Department of Preventive Medicine, University of Southern California, Los Angeles, CA, 90089, USA

    Mariana C. Stern

  6. H. Lee Moffit Cancer Center & Research Institute, Tampa, FL, 33612, USA

    Anna R. Giuliano

  7. Centro de Investigacion En Salud Poblacional, Instituto Nacional de Salud Publica, Av. Universidad No. 655, Col. Sta. Ma. Ahuacatitlan, CP 62100, Cuernavaco, Morelos, Mexico

    Gabriela Torres-Mejia

  8. Department of Bioinformatics and Biostatistics, School of Public Health & Information Sciences, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA

    Guy N. Brock

  9. Department of Internal Medicine, University of Utah, Salt Lake City, UT, 84132, USA

    Roger K. Wolff & Martha L. Slattery

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  1. Stephanie D. Boone
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  2. Kathy B. Baumgartner
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Correspondence to Stephanie D. Boone.

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Boone, S.D., Baumgartner, K.B., Baumgartner, R.N. et al. Associations between genetic variants in the TGF-β signaling pathway and breast cancer risk among Hispanic and non-Hispanic white women. Breast Cancer Res Treat 141, 287–297 (2013). https://doi.org/10.1007/s10549-013-2690-z

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