Comment on Association between Insulin-Like Growth Factor-I (IGF-I) and Bone Mineral Density: Further Evidence Linking IGF-I to Breast Cancer Risk

He Yu

Feist-Weiller Cancer Center Louisiana State University Medical Center Shreveport, Louisiana 71130-3932

The study by Langlois et al. (1) demonstrated an intriguing association between insulin-like growth factor I (IGF-I) and bone mineral density (BMD) in older women. Serum IGF-I levels were positively associated with BMD in all five bone sites, and the association remained statistically significant after potentially confounding factors were adjusted in the analysis, including age, body mass index (BMI), mobility limitation, smoking, and estrogen use. This finding not only suggests the impact of IGF-I on the balance between bone resorption and formation, but also provides evidence to the involvement of IGF-I in breast cancer risk. Both BMD and IGF-I are found to be associated with the risk of the disease.

Cauley et al. (2) reported in 1996 that BMD was associated with the risk of breast cancer in older women. In the study, BMD was measured in five bone sites, including proximal radius, distal radius, calcaneus, total hip, and total spine. The risk of breast cancer was increased significantly with BMD in three of the five bone sites measured. The association was sustained after adjusting for possible confounding factors such as age, BMI, exercise, alcohol consumption, and smoking. When the BMD data was compared between the highest and lowest quartile groups, the increase in breast cancer risk with BMD was significant in all five sites. Given a strong link between estrogen and BMD as well as estrogen’s role in breast cancer, this association was interpreted as an indication of intensive exposure to endogenous estrogens.

Although an alternative explanation of IGF-I in the association of BMD and breast cancer risk was mentioned in the paper, evidence regarding the role of IGFs in breast cancer from epidemiologic studies was not sufficient at that time. Most of the studies were in vitro or in vivo lab experiments. Population-based studies were scarce, only one case-control study and one small clinical study (3, 4). Despite the fact that both of the studies suggested high plasma IGF-I to be associated with an increased risk of breast cancer, a temporal relationship between IGF-I and breast cancer could not be determined, as they were case-control comparisons.

During the past two years, the understanding of IGF in breast cancer has improved substantially. There has been growing evidence linking the IGF family to the development and progression of breast cancer. First, in addition to having strong mitogenic effect on breast cancer cells, IGFs also have antiapoptotic impact on breast cancer cells, thereby facilitating the growth (5). Second, IGFs interact with molecules that are involved in breast cancer. IGFs and estrogens have a synergistic interaction on the growth of breast cancer. Estrogens induce the expression of IGF-I and the IGF-I receptor, and IGFs enhance the transcription activation of estrogen receptor (6). Antiproliferative molecules wild-type p53 protein, retinoic acid, vitamin D, and transforming growth factor ß exert their actions through up-regulating the expression of the IGF binding proteins, which in turn suppress the mitogenic action of IGFs (7, 8, 9). Finally, a recent prospective cohort study demonstrated that high IGF-I levels in plasma were associated with an increased risk of breast cancer (10). Because the blood samples were collected long before the development of the disease, findings from this type of study were more compelling than the case-control studies.

The association of BMD with IGF-I provides further evidence to support the involvement of IGF-I in breast cancer, as the relationship appears to be an additional mechanism, in addition to estrogen, underlying the association between BMD and breast cancer risk. Given the role of IGF-I in breast cancer and the induction of IGF-I production by growth hormone (GH), the recommendation of GH replacement therapy to prevent osteoporosis or to improve other health issues may be premature. More studies are needed to further assess the nature of the relationships among IGF-I, BMD, and breast cancer risk. Determining a safe maximum concentration of IGF-I in blood after balancing the benefits and potential hazards of the molecule would be a crucial issue in future GH replacement therapy.

Footnotes

Address correspondence to: He Yu, M.D., Ph.D., Feist-Weiller Cancer Center, Louisiana State University Medical Center, 1501 Kings Highway, P.O. Box 33932, Shreveport, Louisiana 71130-3932.

Received December 31, 1998.

References

  1. Langlois JA, Rosen CJ, Visser M, et al. 1998 Association between insulin-like growth factor I and bone mineral density in older women and man: the Framingham heart study. J Clin Endocrinol Metab. 83:4257–4262.[Abstract/Free Full Text]
  2. Cauley JA, Lucas FL, Kuller LH, et al. 1996 Bone mineral density and risk of breast cancer in older women. JAMA. 276:1404–1408.[Abstract]
  3. Peyrat JP, Hecquet BB, Vennin P, et al. 1993 Plasma insulin-like growth factor-I (IGF-I) concentrations in human breast cancer. Eur J Cancer. 29A:492–497.
  4. Bruning PF, van Doorn J, Bonfrer JMG, et al. 1995 Insulin-like growth-factor-binding-binding protein 3 is decreased in early-stage operable pre-menopausal breast cancer. Int J Cancer. 62:266–270.[Medline]
  5. Dunn SE, Hardman RA, Kari FW, Barrett JC. 1997 Insulin-like growth factor 1 (IGF-I) alters drug sensitivity of HBL100 human breast cancer cells by inhibition of apoptosis induced by diverse anticancer drugs. Cancer Res. 57:2687–2693.[Abstract]
  6. Ignar-Trowbridge DM, Pimentel M, Malcolm P, et al. 1996 Peptide growth factor cross-talk with the estrogen receptor requires the A/B domain and occurs independently of protein kinase C or estradiol. Endocrinology. 137:1735–1744.[Abstract]
  7. Gucev ZS, Oh Y, Kelley KM, Rosenfeld RG. 1996 Insulin-like growth factor binding protein 3 mediates retinoic acid- and transforming growth factor ß2-induced growth inhibition in human breast cancer cells. Cancer Res. 56:1545–1550.[Abstract]
  8. Xie SP, James SY, Colston KW. 1997 Vitamin D derivatives inhibit the mitogenic effects of IGF-I on MCF-7 human breast cancer cells. J Endocrinol. 154:495–504.[Abstract/Free Full Text]
  9. Buckbinder L, Talbott R, Velasco-Miguel S, et al. 1995 Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature. 377:646–649.[CrossRef][Medline]
  10. Hankinson SE, Willett WC, Colditz GA, et al. 1998 Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet. 351:1393–1396.[CrossRef][Medline]




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