Elsevier

The Lancet

Volume 351, Issue 9113, 9 May 1998, Pages 1393-1396
The Lancet

Articles
Circulating concentrations of insulin-like growth factor I and risk of breast cancer

https://doi.org/10.1016/S0140-6736(97)10384-1Get rights and content

Summary

Background

Insulin-like growth factor (IGF)-I, a mitogenic and antiapoptotic peptide, can affect the proliferation of breast epithelial cells, and is thought to have a role in breast cancer. We hypothesised that high circulating IGF-I concentrations would be associated with an increased risk of breast cancer.

Methods

We carried out a nested case-control study within the prospective Nurses' Health Study cohort. Plasma concentrations of IGF-I and IGF binding protein 3 (IGFBP-3) were measured in blood samples collected in 1989–90. We identified 397 women who had a diagnosis of breast cancer after this date and 620 age-matched controls. IGF-I concentrations were compared by logistic regression with adjustment for other breast-cancer risk factors.

Findings

There was no association between IGF-I concentrations and breast-cancer risk among the whole study group. In postmenopausal women there was no association between IGF-I concentrations and breast-cancer risk (top vs bottom quintile of IGF-I, relative risk 0·85 [95% CI 0·53–1·39]). The relative risk of breast cancer among premenopausal women by IGF-I concentration (top vs bottom tertile) was 2·33 (1·06–5·16; p for trend 0·08). Among premenopausal women less than 50 years old at the time of blood collection, the relative risk was 4·58 (1·75–12·0; p for trend 0·02). After further adjustment for plasma IGFBP-3 concentrations these relative risks were 2·88 and 7·28, respectively.

Interpretation

A positive relation between circulating IGF-I concentration and risk of breast cancer was found among premenopausal but not postmenopausal women. Plasma IGF-I concentrations may be useful in the identification of women at high risk of breast cancer and in the development of risk reduction strategies. Additional larger studies of this association among premenopausal women are needed to provide more precise estimates of effect.

Introduction

There is substantial experimental evidence that the growth hormone/insulin-like growth factor (IGF)-I axis not only affects the proliferative behaviour of breast cancer,1, 2, 3 but also stimulates proliferation of normal breast epithelial cells.4 Transgenic mice that overexpress growth hormone have a high frequency of breast cancer, and overexpression of IGF-I-receptor agonists is associated with cancer and incomplete mammary involution.5, 6, 7 Similarly, rhesus monkeys treated with growth hormone or IGF-I have mammary gland hyperplasia.4 By contrast, ductal hypoplasia is seen in animals that overexpress a growth-hormone antagonist.8, 9 Studies in mice have shown a positive correlation between the strain-specific incidence of breast cancer and the activity of the growth hormone/IGF-I axis.10

There is a large variation between individuals in circulating concentrations of IGF-I and IGF binding protein 3 (IGFBP-3)—the principal IGFBP in the circulation.11, 12 The effect of IGF-I on the proliferation of breast epithelial cells and evidence that increased turnover in certain epithelial-cell populations is associated with a greater risk of neoplastic transformation, led us to investigate the relation of circulating IGF-I concentrations and the risk of breast cancer in women.4, 13

Section snippets

Methods

We carried out a nested case-control study within the Nurses' Health Study cohort. The Nurses' Health Study started in 1976 when 121 700 female registered nurses aged 30–55 years completed and returned a mailed questionnaire. The cohort is assessed every 2 years by questionnaire to update exposure status and to identify newly diagnosed disease. Data have been collected about breast-cancer risk factors such as height, weight, age at menarche, menopause, and at the birth of their first child,

Results

Baseline characteristics of the cases and controls, by menopausal status, are shown in table 1. The mean time between blood collection and diagnosis was 28 months (SD 16) with a range of 1–57 months.

There was a significant relation between IGF-I and age (r=−0·12, p=0·01). IGF-I concentrations did not differ between cases and controls in the whole cohort or among postmenopausal women (table 2). Among premenopausal women younger than 50 years, the mean IGF-I concentration was significantly higher

Discussion

To our knowledge this is the first prospective study to investigate the relation between circulating IGF-I concentrations and risk of breast cancer. We observed a strong positive relation among premenopausal women, particularly after adjusting for concentrations of IGFBP-3, but no association among postmenopausal women.

Two case-control studies18, 21 also found a positive relation between plasma IGF-I concentrations. In the larger study,18 the relation was strongest among premenopausal women

References (36)

  • DL Hadsell et al.

    Targeted expression of des (1–3) human insulin-like growth factor I in transgenic mice influences mammary gland development and IGF-binding protein expression

    Endocrinology

    (1996)
  • P Bates et al.

    Mammary cancer in transgenic mice expressing insulin-like growth factor II (IGF II)

    Br J Cancer

    (1995)
  • NY Chen et al.

    Co-expression of bovine growth hormone (GH) and human GH antagonist genes in transgenic mice

    Endocrinolog

    (1997)
  • W Ruan et al.

    Mammary gland development is impared in transgenic mice overexpressing a bovine growth hormone antagonist

    Proceedings of the Endocrine Society 79th Annual Meeting

    (1997)
  • YN Sinha et al.

    Serum, pituitary and urine concentrations of prolactin and growth hormone in eight strains of mice with varying incidence of mammary tumors

    Int J Cancer

    (1979)
  • A Juul et al.

    Serum insulin-like growth factor I in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index

    J Clin Endocrinol Metab

    (1994)
  • A Juul et al.

    Serum levels of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) in healthy infants, children, and adolescents: the relation to IGF-I, IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index and pubertal maturation

    J Clin Endocrinol Metab

    (1995)
  • SM Cohen et al.

    Cell proliferation in carcinogenesis

    Science

    (1990)
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