Skip to main content

Advertisement

SpringerLink
Log in

Energy homeostasis genes and survival after breast cancer diagnosis: the Breast Cancer Health Disparities Study

  • Original paper
  • Published:
Cancer Causes & Control Aims and scope Submit manuscript

Abstract

Purpose

The leptin-signaling pathway and other genes involved in energy homeostasis (EH) have been examined in relation to breast cancer risk as well as to obesity. We test the hypothesis that genetic variation in EH genes influences survival after diagnosis with breast cancer and that body mass index (BMI) will modify that risk.

Methods

We evaluated associations between 10 EH genes and survival among 1,186 non-Hispanic white and 1,155 Hispanic/Native American women diagnosed with breast cancer. Percent Native American (NA) ancestry was determined from 104 ancestry-informative markers. Adaptive rank truncation product (ARTP) was used to determine gene and pathway significance.

Results

The overall EH pathway was marginally significant for all-cause mortality among women with low NA ancestry (P ARTP = 0.057). Within the pathway, ghrelin (GHRL) and leptin receptor (LEPR) were significantly associated with all-cause mortality (P ARTP = 0.035 and 0.007, respectively). The EH pathway was significantly associated with breast cancer-specific mortality among women with low NA ancestry (P ARTP = 0.038). Three genes cholecystokinin (CCK), GHRL, and LEPR were significantly associated with breast cancer-specific mortality among women with low NA ancestry (P ARTP = 0.046, 0.015, and 0.046, respectively), while neuropeptide Y (NPY) was significantly associated with breast cancer-specific mortality among women with higher NA ancestry (P ARTP = 0.038). BMI did not modify these associations.

Conclusions

Our data support our hypothesis that certain EH genes influence survival after diagnosis with breast cancer; associations appear to be most important among women with low NA ancestry.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Fusco R, Galgani M, Procaccini C, Franco R, Pirozzi G, Fucci L et al (2010) Cellular and molecular crosstalk between leptin receptor and estrogen receptor-{alpha} in breast cancer: molecular basis for a novel therapeutic setting. Endocr Relat Cancer 17(2):373–382

    Article  CAS  PubMed  Google Scholar 

  2. Llanos AA, Dumitrescu RG, Marian C, Makambi KH, Spear SL, Kallakury BV et al (2012) Adipokines in plasma and breast tissues: associations with breast cancer risk factors. Cancer Epidemiol Biomarkers Prev 21(10):1745–1755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dossus L, McKay JD, Canzian F, Wilkening S, Rinaldi S, Biessy C et al (2008) Polymorphisms of genes coding for ghrelin and its receptor in relation to anthropometry, circulating levels of IGF-I and IGFBP-3, and breast cancer risk: a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Carcinogenesis 29(7):1360–1366

    Article  CAS  PubMed  Google Scholar 

  4. Lim CT, Kola B, Grossman A, Korbonits M (2011) The expression of ghrelin O-acyltransferase (GOAT) in human tissues. Endocr J 58(8):707–710

    Article  CAS  PubMed  Google Scholar 

  5. Cleveland RJ, Gammon MD, Long CM, Gaudet MM, Eng SM, Teitelbaum SL et al (2010) Common genetic variations in the LEP and LEPR genes, obesity and breast cancer incidence and survival. Breast Cancer Res Treat 120(3):745–752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Duggan C, Irwin ML, Xiao L, Henderson KD, Smith AW, Baumgartner RN et al (2011) Associations of insulin resistance and adiponectin with mortality in women with breast cancer. J Clin Oncol 29(1):32–39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sheriff S, Ali M, Yahya A, Haider KH, Balasubramaniam A, Amlal H (2010) Neuropeptide Y Y5 receptor promotes cell growth through extracellular signal-regulated kinase signaling and cyclic AMP inhibition in a human breast cancer cell line. Mol Cancer Res 8(4):604–614

    Article  CAS  PubMed  Google Scholar 

  8. Stefanaki C, Rorris F-P, Stamatakos M (2012) The role of ghrelin signals in breast cancer: a systematic review. Curr Signal Transduct Ther 7:2470253

    Article  Google Scholar 

  9. Wu JT, Kral JG (2004) Ghrelin: integrative neuroendocrine peptide in health and disease. Ann Surg 239(4):464–474

    Article  PubMed  PubMed Central  Google Scholar 

  10. Dutta D, Ghosh S, Pandit K, Mukhopadhyay P, Chowdhury S (2012) Leptin and cancer: pathogenesis and modulation. Indian J Endocrinol Metab 16(Suppl 3):S596–S600

    PubMed  PubMed Central  Google Scholar 

  11. Hardwick JC, Van Den Brink GR, Offerhaus GJ, Van Deventer SJ, Peppelenbosch MP (2001) Leptin is a growth factor for colonic epithelial cells. Gastroenterology 121(1):79–90

    Article  CAS  PubMed  Google Scholar 

  12. Rose DP, Gilhooly EM, Nixon DW (2002) Adverse effects of obesity on breast cancer prognosis, and the biological actions of leptin (review). Int J Oncol 21(6):1285–1292

    CAS  PubMed  Google Scholar 

  13. Gronberg M, Fjallskog ML, Jirstrom K, Janson ET (2012) Expression of ghrelin is correlated to a favorable outcome in invasive breast cancer. Acta Oncol 51(3):386–393

    Article  PubMed  Google Scholar 

  14. Mondello P, Lacquaniti A, Mondello S, Bolignano D, Pitini V, Aloisi C et al (2014) Emerging markers of cachexia predict survival in cancer patients. BMC Cancer 14:828

    Article  PubMed  PubMed Central  Google Scholar 

  15. Slattery ML, Lundgreen A, Hines L, Wolff RK, Torres-Mejia G, Baumgartner KN, John EM (2015) Energy homeostasis genes and breast cancer risk: the influence of ancestry, body size, and menopausal status, the Breast Cancer Health Disparities Study. Cancer Epidemiol. doi:10.1016/j.canep.2015.08.012

  16. Slattery ML, Lundgreen A, Stern MC, Hines L, Wolff RK, Giuliano AR et al (2014) The influence of genetic ancestry and ethnicity on breast cancer survival associated with genetic variation in the TGF-beta-signaling pathway: the Breast Cancer Health Disparities Study. Cancer Causes Control 25(3):293–307

    Article  PubMed  PubMed Central  Google Scholar 

  17. Slattery ML, John EM, Torres-Mejia G, Lundgreen A, Herrick JS, Baumgartner KB et al (2012) Genetic variation in genes involved in hormones, inflammation and energetic factors and breast cancer risk in an admixed population. Carcinogenesis 33(8):1512–1521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kwan ML, John EM, Caan BJ, Lee VS, Bernstein L, Cheng I et al (2014) Obesity and mortality after breast cancer by race/ethnicity: the California Breast Cancer Survivorship Consortium. Am J Epidemiol 179(1):95–111

    Article  PubMed  PubMed Central  Google Scholar 

  19. John EM, Sangaramoorthy M, Hines LM, Stern MC, Baumgartner KB, Giuliano AR et al (2015) Body size throughout adult life influences postmenopausal breast cancer risk among Hispanic women: the Breast Cancer Health Disparities Study. Cancer Epidemiol Biomarkers Prev 24(1):128–137

    Article  PubMed  PubMed Central  Google Scholar 

  20. John EM, Sangaramoorthy M, Hines LM, Stern MC, Baumgartner KB, Giuliano AR et al (2015) Overall and abdominal adiposity and premenopausal breast cancer risk among Hispanic women: the Breast Cancer Health Disparities Study. Cancer Epidemiol Biomarkers Prev. 24(1):138–147

    Article  PubMed  PubMed Central  Google Scholar 

  21. Slattery ML, Sweeney C, Edwards S, Herrick J, Baumgartner K, Wolff R et al (2007) Body size, weight change, fat distribution and breast cancer risk in Hispanic and non-Hispanic white women. Breast Cancer Res Treat 102(1):85–101

    Article  PubMed  Google Scholar 

  22. John EM, Horn-Ross PL, Koo J (2003) Lifetime physical activity and breast cancer risk in a multiethnic population: the San Francisco Bay area breast cancer study. Cancer Epidemiol Biomarkers Prev 12(11 Pt 1):1143–1152

    PubMed  Google Scholar 

  23. John EM, Phipps AI, Davis A, Koo J (2005) Migration history, acculturation, and breast cancer risk in Hispanic women. Cancer Epidemiol Biomarkers Prev 14(12):2905–2913

    Article  PubMed  Google Scholar 

  24. Falush D, Stephens M, Pritchard JK (2003) Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 164(4):1567–1587

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Pritchard JK, Stephens M, Donnelly P (2000) Inference of population structure using multilocus genotype data. Genetics 155(2):945–959

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Yu K, Li Q, Bergen AW, Pfeiffer RM, Rosenberg PS, Caporaso N et al (2009) Pathway analysis by adaptive combination of P-values. Genet Epidemiol 33(8):700–709

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kai Yu OL, Wheeler W (2011) ARTP gene and pathway p-values computed using the adaptive rank truncated product. 2.0.0 pp. R package

  28. Nyholt DR (2004) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74(4):765–769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Li J, Ji L (2005) Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity 95(3):221–227

    Article  CAS  PubMed  Google Scholar 

  30. Scholz C, Andergassen U, Hepp P, Schindlbeck C, Friedl TW, Harbeck N et al (2015) Obesity as an independent risk factor for decreased survival in node-positive high-risk breast cancer. Breast Cancer Res Treat 151(3):569–576

    Article  CAS  PubMed  Google Scholar 

  31. Taghizadeh N, Boezen HM, Schouten JP, Schroder CP, Vries EG, Vonk JM (2015) BMI and lifetime changes in BMI and cancer mortality risk. PLoS ONE 10(4):e0125261

    Article  PubMed  PubMed Central  Google Scholar 

  32. Herlevic VC, Mowad R, Miller JK, Darensburg NA, Li BD, Kim RH (2015) Breast cancer outcomes in a population with high prevalence of obesity. J Surg Res. doi:10.1016/j.jss.2015.03.088

  33. Shin A, Ren Z, Shu XO, Cai Q, Gao YT, Zheng W (2007) Expression patterns of insulin-like growth factor 1 (IGF-I) and its receptor in mammary tissues and their associations with breast cancer survival. Breast Cancer Res Treat 105(1):55–61

    Article  CAS  PubMed  Google Scholar 

  34. Muendlein A, Lang AH, Geller-Rhomberg S, Winder T, Gasser K, Drexel H et al (2013) Association of a common genetic variant of the IGF-1 gene with event-free survival in patients with HER2-positive breast cancer. J Cancer Res Clin Oncol 139(3):491–498

    Article  CAS  PubMed  Google Scholar 

  35. Yeh AH, Jeffery PL, Duncan RP, Herington AC, Chopin LK (2005) Ghrelin and a novel preproghrelin isoform are highly expressed in prostate cancer and ghrelin activates mitogen-activated protein kinase in prostate cancer. Clin Cancer Res 11(23):8295–8303

    Article  CAS  PubMed  Google Scholar 

  36. Slattery ML, Hines LH, Lundgreen A, Baumgartner KB, Wolff RK, Stern MC et al (2014) Diet and lifestyle factors interact with MAPK genes to influence survival: the Breast Cancer Health Disparities Study. Cancer Causes Control 25(9):1211–1225

    Article  PubMed  PubMed Central  Google Scholar 

  37. Zheng Q, Banaszak L, Fracci S, Basali D, Dunlap SM, Hursting SD et al (2013) Leptin receptor maintains cancer stem-like properties in triple negative breast cancer cells. Endocr Relat Cancer 20(6):797–808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Garcia-Robles MJ, Segura-Ortega JE, Fafutis-Morris M (2013) The biology of leptin and its implications in breast cancer: a general view. J Interferon Cytokine Res 33(12):717–727

    Article  CAS  PubMed  Google Scholar 

  39. Terrasi M, Bazan V, Caruso S, Insalaco L, Amodeo V, Fanale D et al (2013) Effects of PPARγ agonists on the expression of leptin and vascular endothelial growth factor in breast cancer cells. J Cell Physiol 228(6):1368–1374

    Article  CAS  PubMed  Google Scholar 

  40. Snoussi K, Strosberg AD, Bouaouina N, Ben Ahmed S, Helal AN, Chouchane L (2006) Leptin and leptin receptor polymorphisms are associated with increased risk and poor prognosis of breast carcinoma. BMC Cancer 6:38

    Article  PubMed  PubMed Central  Google Scholar 

  41. Miller PC, Clarke J, Koru-Sengul T, Brinkman J, El-Ashry D (2015) A novel MAPK-microRNA signature is predictive of hormone-therapy resistance and poor outcome in ER-positive breast cancer. Clin Cancer Res 21(2):373–385

    Article  CAS  PubMed  Google Scholar 

  42. Gee JM, Robertson JF, Ellis IO, Nicholson RI (2001) Phosphorylation of ERK1/2 mitogen-activated protein kinase is associated with poor response to anti-hormonal therapy and decreased patient survival in clinical breast cancer. Int J Cancer 95(4):247–254

    Article  CAS  PubMed  Google Scholar 

  43. Ribeiro JA, Serquiz AC, Silva PF, Barbosa PB, Sampaio TB, Araujo Junior RF et al (2015) Trypsin inhibitor from Tamarindus indica L. seeds reduces weight gain and food consumption and increases plasmatic cholecystokinin levels. Clinics 70(2):136–143

    Article  PubMed  Google Scholar 

  44. Pivovarova O, Hornemann S, Weimer S, Lu Y, Murahovschi V, Zhuk S et al (2015) Regulation of nutrition-associated receptors in blood monocytes of normal weight and obese humans. Peptides 65:12–19

    Article  CAS  PubMed  Google Scholar 

  45. Linnemann AK, Neuman JC, Battiola TJ, Wisinski JA, Kimple ME, Davis DB (2015) Glucagon-like peptide-1 regulates cholecystokinin production in beta-cells to protect from apoptosis. Mol Endocrinol. doi:10.1210/me.2015-1030

    PubMed  Google Scholar 

  46. Medeiros PJ, Jackson DN (2013) Neuropeptide Y Y5-receptor activation on breast cancer cells acts as a paracrine system that stimulates VEGF expression and secretion to promote angiogenesis. Peptides 48:106–113

    Article  CAS  PubMed  Google Scholar 

  47. Medeiros PJ, Al-Khazraji BK, Novielli NM, Postovit LM, Chambers AF, Jackson DN (2012) Neuropeptide Y stimulates proliferation and migration in the 4T1 breast cancer cell line. Int J Cancer 131(2):276–286

    Article  CAS  PubMed  Google Scholar 

  48. Korner M, Reubi JC (2007) NPY receptors in human cancer: a review of current knowledge. Peptides 28(2):419–425

    Article  PubMed  Google Scholar 

  49. Lonne GK, Masoumi KC, Lennartsson J, Larsson C (2009) Protein kinase Cdelta supports survival of MDA-MB-231 breast cancer cells by suppressing the ERK1/2 pathway. J Biol Chem 284(48):33456–33465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Slattery ML, John EM, Torres-Mejia G, Lundgreen A, Lewinger JP, Stern MC et al (2014) Angiogenesis genes, dietary oxidative balance and breast cancer risk and progression: the Breast Cancer Health Disparities Study. Int J Cancer 134(3):629–644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Slattery ML, Lundgreen A, Torres-Mejia G, Wolff RK, Hines L, Baumgartner K et al (2014) Diet and lifestyle factors modify immune/inflammation response genes to alter breast cancer risk and prognosis: the Breast Cancer Health Disparities Study. Mutat Res 770:19–28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We would also like to acknowledge the contributions of the following individuals to the study: Sandra Edwards and Jennifer Herrick for data harmonization and management; Erica Wolff and Michael Hoffman for laboratory support; Jocelyn Koo for data management for the San Francisco Bay Area Breast Cancer Study; Dr. Tim Byer, Dr. Kathy Baumgartner, and Dr. Anna Giuliano for their contribution to the 4-Corners Breast Cancer Study; and Dr. Josh Galanter for assistance in selection of AIMs markers.

Funding

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 US 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-Corners 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.

Author information

Authors and Affiliations

  1. Department of Medicine, University of Utah, 383 Colorow, Salt Lake City, UT, 84108, USA

    Andrew J. Pellatt, Abbie Lundgreen, Roger K. Wolff & Martha L. Slattery

  2. Department of Biology, University of Colorado at Colorado Springs, 1420 Austin Bluffs Parkway, Colorado Springs, CO, 80918, USA

    Lisa Hines

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

    Esther M. John

  4. Department of Health Research and Policy (Epidemiology), Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Esther M. John

Authors
  1. Andrew J. Pellatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abbie Lundgreen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roger K. Wolff
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lisa Hines
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Esther M. John
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martha L. Slattery
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martha L. Slattery.

Ethics declarations

Conflict of interest

The authors have no conflict of interest to report.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 20 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pellatt, A.J., Lundgreen, A., Wolff, R.K. et al. Energy homeostasis genes and survival after breast cancer diagnosis: the Breast Cancer Health Disparities Study. Cancer Causes Control 27, 47–57 (2016). https://doi.org/10.1007/s10552-015-0681-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10552-015-0681-6

Keywords

Search

Navigation