Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women

Marc J. Gunter, Donald R. Hoover, Herbert Yu, Sylvia Wassertheil-Smoller, Thomas E. Rohan, Joann E. Manson, Jixin Li, Gloria Y F Ho, Xiaonan (Nan) Xue, Garnet L. Anderson, Robert C. Kaplan, Tiffany G. Harris, Barbara V. Howard, Judith Wylie-Rosett, Robert D. Burk, Howard Strickler

Research output: Contribution to journalArticle

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Abstract

Background: The positive association between obesity and postmenopausal breast cancer has been attributed, in part, to the fact that estrogen, a risk factor for breast cancer, is synthesized in adipose tissue. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed associations between circulating levels of insulin and/or insulin-like growth factor (IGF)-I, a related hormone, and the risk of breast cancer independent of estrogen level.Methods: We conducted a case-cohort study of incident breast cancer among nondiabetic women who were enrolled in the Women's Health Initiative Observational Study (WHI-OS), a prospective cohort of 93 676 postmenopausal women. Fasting serum samples obtained at study entry from 835 incident breast cancer case subjects and from a subcohort of 816 randomly chosen WHI-OS subjects were tested for levels of insulin, glucose, total IGF-I, free IGF-I, insulin-like growth factor binding protein-3, and estradiol. Multivariable Cox proportional hazards models were used to estimate associations between levels of the serologic factors and baseline characteristics (including body mass index [BMI]) and the risk of breast cancer. All statistical tests were two-sided.Results: Insulin levels were positively associated with the risk of breast cancer (hazard ratio [HR] for highest vs lowest quartile of insulin level = 1.46, 95% confidence interval [CI] = 1.00 to 2.13, Ptrend =. 02); however, the association with insulin level varied by hormone therapy (HT) use (Pinteraction =. 01). In a model that controlled for multiple breast cancer risk factors including estradiol, insulin level was associated with breast cancer only among nonusers of HT (HR for highest vs lowest quartile of insulin level = 2.40, 95% CI = 1.30 to 4.41, Ptrend <. 001). Obesity (BMI ≥30 kg/m2) was also associated with the risk of breast cancer among nonusers of HT (HR for BMI ≥30 kg/m2 vs 18.5 to <25 kg/m2 = 2.12, 95% CI = 1.26 to 3.58, Ptrend =. 003); however, this association was attenuated by adjustment for insulin (Ptrend =. 40).Conclusion: These data suggest that hyperinsulinemia is an independent risk factor for breast cancer and may have a substantial role in explaining the obesity-breast cancer relationship.

Original languageEnglish (US)
Pages (from-to)48-60
Number of pages13
JournalJournal of the National Cancer Institute
Volume101
Issue number1
DOIs
StatePublished - Jan 2009

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Insulin-Like Growth Factor I
Insulin
Breast Neoplasms
Obesity
Hormones
Body Mass Index
Women's Health
Confidence Intervals
Observational Studies
Estradiol
Estrogens
Insulin-Like Growth Factor Binding Protein 3
Hyperinsulinism
Mitogens
Proportional Hazards Models
Adipose Tissue
Fasting
Cohort Studies
Therapeutics
Prospective Studies

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. / Gunter, Marc J.; Hoover, Donald R.; Yu, Herbert; Wassertheil-Smoller, Sylvia; Rohan, Thomas E.; Manson, Joann E.; Li, Jixin; Ho, Gloria Y F; Xue, Xiaonan (Nan); Anderson, Garnet L.; Kaplan, Robert C.; Harris, Tiffany G.; Howard, Barbara V.; Wylie-Rosett, Judith; Burk, Robert D.; Strickler, Howard.

In: Journal of the National Cancer Institute, Vol. 101, No. 1, 01.2009, p. 48-60.

Research output: Contribution to journalArticle

Gunter, MJ, Hoover, DR, Yu, H, Wassertheil-Smoller, S, Rohan, TE, Manson, JE, Li, J, Ho, GYF, Xue, XN, Anderson, GL, Kaplan, RC, Harris, TG, Howard, BV, Wylie-Rosett, J, Burk, RD & Strickler, H 2009, 'Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women', Journal of the National Cancer Institute, vol. 101, no. 1, pp. 48-60. https://doi.org/10.1093/jnci/djn415
Gunter, Marc J. ; Hoover, Donald R. ; Yu, Herbert ; Wassertheil-Smoller, Sylvia ; Rohan, Thomas E. ; Manson, Joann E. ; Li, Jixin ; Ho, Gloria Y F ; Xue, Xiaonan (Nan) ; Anderson, Garnet L. ; Kaplan, Robert C. ; Harris, Tiffany G. ; Howard, Barbara V. ; Wylie-Rosett, Judith ; Burk, Robert D. ; Strickler, Howard. / Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. In: Journal of the National Cancer Institute. 2009 ; Vol. 101, No. 1. pp. 48-60.
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abstract = "Background: The positive association between obesity and postmenopausal breast cancer has been attributed, in part, to the fact that estrogen, a risk factor for breast cancer, is synthesized in adipose tissue. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed associations between circulating levels of insulin and/or insulin-like growth factor (IGF)-I, a related hormone, and the risk of breast cancer independent of estrogen level.Methods: We conducted a case-cohort study of incident breast cancer among nondiabetic women who were enrolled in the Women's Health Initiative Observational Study (WHI-OS), a prospective cohort of 93 676 postmenopausal women. Fasting serum samples obtained at study entry from 835 incident breast cancer case subjects and from a subcohort of 816 randomly chosen WHI-OS subjects were tested for levels of insulin, glucose, total IGF-I, free IGF-I, insulin-like growth factor binding protein-3, and estradiol. Multivariable Cox proportional hazards models were used to estimate associations between levels of the serologic factors and baseline characteristics (including body mass index [BMI]) and the risk of breast cancer. All statistical tests were two-sided.Results: Insulin levels were positively associated with the risk of breast cancer (hazard ratio [HR] for highest vs lowest quartile of insulin level = 1.46, 95{\%} confidence interval [CI] = 1.00 to 2.13, Ptrend =. 02); however, the association with insulin level varied by hormone therapy (HT) use (Pinteraction =. 01). In a model that controlled for multiple breast cancer risk factors including estradiol, insulin level was associated with breast cancer only among nonusers of HT (HR for highest vs lowest quartile of insulin level = 2.40, 95{\%} CI = 1.30 to 4.41, Ptrend <. 001). Obesity (BMI ≥30 kg/m2) was also associated with the risk of breast cancer among nonusers of HT (HR for BMI ≥30 kg/m2 vs 18.5 to <25 kg/m2 = 2.12, 95{\%} CI = 1.26 to 3.58, Ptrend =. 003); however, this association was attenuated by adjustment for insulin (Ptrend =. 40).Conclusion: These data suggest that hyperinsulinemia is an independent risk factor for breast cancer and may have a substantial role in explaining the obesity-breast cancer relationship.",
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T1 - Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women

AU - Gunter, Marc J.

AU - Hoover, Donald R.

AU - Yu, Herbert

AU - Wassertheil-Smoller, Sylvia

AU - Rohan, Thomas E.

AU - Manson, Joann E.

AU - Li, Jixin

AU - Ho, Gloria Y F

AU - Xue, Xiaonan (Nan)

AU - Anderson, Garnet L.

AU - Kaplan, Robert C.

AU - Harris, Tiffany G.

AU - Howard, Barbara V.

AU - Wylie-Rosett, Judith

AU - Burk, Robert D.

AU - Strickler, Howard

PY - 2009/1

Y1 - 2009/1

N2 - Background: The positive association between obesity and postmenopausal breast cancer has been attributed, in part, to the fact that estrogen, a risk factor for breast cancer, is synthesized in adipose tissue. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed associations between circulating levels of insulin and/or insulin-like growth factor (IGF)-I, a related hormone, and the risk of breast cancer independent of estrogen level.Methods: We conducted a case-cohort study of incident breast cancer among nondiabetic women who were enrolled in the Women's Health Initiative Observational Study (WHI-OS), a prospective cohort of 93 676 postmenopausal women. Fasting serum samples obtained at study entry from 835 incident breast cancer case subjects and from a subcohort of 816 randomly chosen WHI-OS subjects were tested for levels of insulin, glucose, total IGF-I, free IGF-I, insulin-like growth factor binding protein-3, and estradiol. Multivariable Cox proportional hazards models were used to estimate associations between levels of the serologic factors and baseline characteristics (including body mass index [BMI]) and the risk of breast cancer. All statistical tests were two-sided.Results: Insulin levels were positively associated with the risk of breast cancer (hazard ratio [HR] for highest vs lowest quartile of insulin level = 1.46, 95% confidence interval [CI] = 1.00 to 2.13, Ptrend =. 02); however, the association with insulin level varied by hormone therapy (HT) use (Pinteraction =. 01). In a model that controlled for multiple breast cancer risk factors including estradiol, insulin level was associated with breast cancer only among nonusers of HT (HR for highest vs lowest quartile of insulin level = 2.40, 95% CI = 1.30 to 4.41, Ptrend <. 001). Obesity (BMI ≥30 kg/m2) was also associated with the risk of breast cancer among nonusers of HT (HR for BMI ≥30 kg/m2 vs 18.5 to <25 kg/m2 = 2.12, 95% CI = 1.26 to 3.58, Ptrend =. 003); however, this association was attenuated by adjustment for insulin (Ptrend =. 40).Conclusion: These data suggest that hyperinsulinemia is an independent risk factor for breast cancer and may have a substantial role in explaining the obesity-breast cancer relationship.

AB - Background: The positive association between obesity and postmenopausal breast cancer has been attributed, in part, to the fact that estrogen, a risk factor for breast cancer, is synthesized in adipose tissue. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed associations between circulating levels of insulin and/or insulin-like growth factor (IGF)-I, a related hormone, and the risk of breast cancer independent of estrogen level.Methods: We conducted a case-cohort study of incident breast cancer among nondiabetic women who were enrolled in the Women's Health Initiative Observational Study (WHI-OS), a prospective cohort of 93 676 postmenopausal women. Fasting serum samples obtained at study entry from 835 incident breast cancer case subjects and from a subcohort of 816 randomly chosen WHI-OS subjects were tested for levels of insulin, glucose, total IGF-I, free IGF-I, insulin-like growth factor binding protein-3, and estradiol. Multivariable Cox proportional hazards models were used to estimate associations between levels of the serologic factors and baseline characteristics (including body mass index [BMI]) and the risk of breast cancer. All statistical tests were two-sided.Results: Insulin levels were positively associated with the risk of breast cancer (hazard ratio [HR] for highest vs lowest quartile of insulin level = 1.46, 95% confidence interval [CI] = 1.00 to 2.13, Ptrend =. 02); however, the association with insulin level varied by hormone therapy (HT) use (Pinteraction =. 01). In a model that controlled for multiple breast cancer risk factors including estradiol, insulin level was associated with breast cancer only among nonusers of HT (HR for highest vs lowest quartile of insulin level = 2.40, 95% CI = 1.30 to 4.41, Ptrend <. 001). Obesity (BMI ≥30 kg/m2) was also associated with the risk of breast cancer among nonusers of HT (HR for BMI ≥30 kg/m2 vs 18.5 to <25 kg/m2 = 2.12, 95% CI = 1.26 to 3.58, Ptrend =. 003); however, this association was attenuated by adjustment for insulin (Ptrend =. 40).Conclusion: These data suggest that hyperinsulinemia is an independent risk factor for breast cancer and may have a substantial role in explaining the obesity-breast cancer relationship.

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