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Association between germline single nucleotide polymorphisms in the PI3K-AKT-mTOR pathway, obesity, and breast cancer disease-free survival

Breast Cancer Research and Treatment volume 147, pages 381–387 (2014)Cite this article

Abstract

Obesity-related hormones and cytokines alter PI3 K-AKT-mTOR pathway activation in breast tumors contributing to poorer disease-free survival (DFS) and decreased responsiveness to tamoxifen and trastuzumab. We hypothesized that single nucleotide polymorphisms (SNPs) in candidate genes in the PI3 K-AKT-mTOR signaling pathway may act as genetic modifiers of breast cancer DFS. We analyzed the association of 106 tagging SNPs in 13 genes (ADIPOQ, IGF1, INS, IRS1, LEP, LEPR, LEPROT, PIK3CA, PIK3R5, PTEN, TSC1, TSC2, and AKT1) in the P13K-AKT-mTOR pathway with DFS in a sample of 1,019 women with stage I–II breast cancer. SNPs significantly associated with DFS in any genetic model (additive, dominant, or recessive) after correcting for false discovery rate (FDR = 0.10) were included in Cox proportional hazards multivariable analyses. After adjusting for race/ethnicity, age at diagnosis, tumor stage, and treatment, rs1063539 in ADIPOQ, rs11585329 in LEPR, and rs2519757 in TSC1 were associated with improved DFS, and rs1520220 in IGF1 and rs2677760 in PIK3CA were associated with worse DFS. The associations were not significantly modified by the type of systemic treatment received or body mass index. The SNPs were not associated with tumor characteristics such as tumor size, lymph node status, nuclear grade, or hormone receptor status. In this study, germline SNPs in the PI3 K-AKT-mTOR pathway were associated with breast cancer DFS and may be potential prognostic markers. Future studies are needed to replicate our results and to evaluate the relationship between these polymorphisms and activation of the PI3 K-AKT-mTOR pathway in breast tumors.

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Fig. 1

Abbreviations

PI3K:

Phosphatidylinositol-3 kinase

mTOR:

Mammalian target of rapamycin

ADIPOQ:

AdiponectinC1Q and collagen domain containing

IGF1:

Insulin-like growth factor 1

INS:

Insulin

IRS1:

Insulin receptor substrate 1LEP: Leptin

LEPR:

Leptin receptorLEPROT: Leptin receptor overlapping transcript

mTOR:

Mammalian target of rapamycin

mTORC1:

Mammalian target of rapamycin complex 1

PIK3CA:

Phosphatidylinositol-45-bisphosphate 3-kinase, catalytic subunit alpha

PIK3R5:

Phosphoinositide-3-kinaseregulatory subunit 5

PTEN:

Phosphatase and tensin homolog

TSC1:

Tuberous sclerosis 1

TSC2:

Tuberous sclerosis 2

AKT1:

V-Akt murine thymoma viral oncogene homolog 1

SNP:

Single nucleotide polymorphism

DFS:

Disease-free survival

ESBCR:

Early stage breast cancer repository

ER:

Estrogen receptor

PR:

Progesterone receptor

MAF:

Minor allele frequency

LD:

Linkage disequilibrium

HR:

Hazard ratio

CI:

Confidence interval

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Acknowledgments

This research was supported by the following grants–Susan Komen Career Catalyst Disparities Award (AMB), Komen Foundation Promise and SAC grant (GBM), Susan G. Komen for the Cure SAC110047 and SAB0800007 (MB), National Breast Cancer Foundation, and the National Cancer Institute at the NIH SPORE P50CA116199 (MB), National Institutes of Health R01 CA089608 (MB and PT), and National Institutes of Health K07 CA160753 (MP).

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Authors and Affiliations

  1. Department of Gastroenterology – Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Mala Pande

  2. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Melissa L. Bondy

  3. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Kim-Anh Do & Jun Ying

  4. Department of Pathology Systems, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Aysegul A. Sahin

  5. Department of Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Gordon B. Mills

  6. Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, tucson, AZ, 85719, USA

    Patricia A. Thompson

  7. Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Abenaa M. Brewster

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  1. Mala Pande
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  2. Melissa L. Bondy
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Correspondence to Abenaa M. Brewster.

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Pande, M., Bondy, M.L., Do, KA. et al. Association between germline single nucleotide polymorphisms in the PI3K-AKT-mTOR pathway, obesity, and breast cancer disease-free survival. Breast Cancer Res Treat 147, 381–387 (2014). https://doi.org/10.1007/s10549-014-3081-9

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  • DOI: https://doi.org/10.1007/s10549-014-3081-9

Keywords

  • Breast cancer
  • Prognosis
  • PI3 K-AKT-mTOR pathway
  • Single nucleotide polymorphisms
  • Disease-free survival