Study Suggests IGF-1 Plays 'Causal Role' in
Breast Cancer

March 18, 2020

Women with high levels of insulin-like growth factor 1 (IGF-1) may be at increased risk for breast cancer, according to results of a study that used both epidemiological techniques as well as genetic analyses.

The results were published online March 11 in Annals of Oncology

"Taken together, these results provide the strongest evidence to date for a causal role of the IGF-pathway in breast cancer development," said senior author Marc Gunter, PhD, head of the nutritional epidemiology group at the International Agency for Research on Cancer (IARC) in Lyon, France.

The results also "suggest that altering IGF-1 levels through diet and lifestyle or pharmacological means may be an effective strategy in the primary prevention of breast cancer," he added in a press statement.

IGF-1 Increased by Many Factors, Including Milk

IGF-1 is a hormone that is similar to insulin and helps promote growth, especially during puberty. The hormone has wide-ranging effects and stimulates growth of many different types of cells in the body. Various factors may increase IGF-1 levels, including a high-protein diet, pregnancy, and some disease processes, the researchers note.

Recently, some scientists have been interested in IGF-1 because of a possible link between cow's milk and breast cancer. Dairy cows have been bred to have higher levels of IGF-1. Most are also pregnant and, by definition, lactating. So the milk they produce has increased levels of progestins and estrogen. Researchers have speculated that higher levels of IGF-1, estrogen, and progestins in cow's milk may play a role in the development of breast cancer, as recently reported by Medscape Medical News.

Largest Study to Date

"To our knowledge, this is largest single study and the first Mendelian randomization study to examine the relationship between IGF-1 and breast cancer," Gunter said. 

Mendelian randomization uses complex statistical techniques to evaluate genes and their causal effect on disease. In this case, researchers evaluated genes related to IGF-1 levels, and whether variations in these genes were linked to different risks for breast cancer.

"Our Mendelian randomization analyses yielded strikingly similar positive associations between IGF-1 and breast cancer as those found in our observational analyses," Gunter said.

"The association between IGF-1 and breast cancer was first investigated in the 1980s, and our findings are in line with various studies since then. But clarifying the direction of the association using Mendelian randomization in our study leads the way for research into how the IGF-1 pathway can be harnessed in breast cancer prevention," coauthor Anika Knüppel, PhD, said in the same press statement. Knüppel is a nutritional epidemiologist at the University of Oxford, United Kingdom.

The next step is to investigate lifestyle factors that may affect IGF-1 levels, and how changing these factors could decrease breast cancer risk. Drugs may also affect IGF-1 levels, but their safety, effectiveness, and length of use would need more study, according to the authors.

Study Details 

For the observational part of their study, these researchers used data from 206,263 women in the UK Biobank, which looked at genetic and environmental contributions to disease in women aged 40 to 69 years. The current analysis included women who were cancer-free and had their blood levels of IGF-1 checked when they entered the study between 2006 and 2010. Information on cancer diagnoses came from national cancer registries and death records.

Over a median follow-up of 7.1 years, 4360 women (2% of the 206,263 total) were diagnosed with breast cancer.

The team adjusted the analyses for age, poverty, 10 common risk factors for breast cancer, and biological factors that may affect IGF-1 levels. After these adjustments, the results showed that women with the highest levels of IGF-1 (≥ 25.6 nmol/L) had a 24% increased risk of breast cancer, compared to women with the lowest IGF-1 levels (<16.4 nmol/L) (hazard ratio [HR] for highest vs lowest fifth, 1.24; 95% confidence interval [CI], 1.12 - 1.37; P trend < .0001).

The researchers also used data from 6711 women with repeat IGF-1 measurements to conduct analyses that adjusted for variation in IGF-1 over time. Results showed that the risk of breast cancer increased by 11% for each 5 nmol/L increase in IGF-1 levels (HR, 1.11; 95% CI, 1.07 - 1.16).

Results did not differ by menopausal status, follow-up time, and common risk factors for breast cancer such as body mass index (P heterogeneity > .08)

In the Mendelian randomization part of the study, the researchers evaluated single nucleotide polymorphisms (SNPs), or genetic variants that involve changes in just one base pair of DNA and do not cause disease. Specifically, they analyzed 265 SNPs linked to blood levels of IGF-1, and four SNPs for insulin-like growth factor binding protein 3 (IGFBP-3), which binds most of the IGF-1 found in the blood. Some studies have found that IGFBP-3 may inhibit cell growth.

Finally, they used data from the Breast Cancer Association Consortium (BCAC) to look for associations between these SNPs and breast cancer in 122,977 individuals with breast cancer and 105,974 individuals (control group) without breast cancer.

Results showed that for each 5 nmol/L increase in genetically-predicted IGF-1 levels, the odds of developing breast cancer increased by 5% (odds ratio [OR], 1.05; 95% CI, 1.01 - 1.10; P = .02).

Results were similar for estrogen receptor-positive breast cancer, for which the odds increased by 6% for each 5 nmol/L increase in genetically-predicted IGF-1 levels (OR, 1.06; 95% CI, 1.01 - 1.11; P = .03).

However, the results showed no association between genetically predicted IGF-1 levels and estrogen receptor-negative breast cancer (OR, 1.02; 95% CI, 0.96 - 1.08; P = .58).

Results also showed no link between genetically predicted IGFBP-3 levels and breast cancer (OR per 1-standard deviation increment, 1.00; 95% CI, 0.97 - 1.04; P = .98).

Additional analyses showed little evidence for the role of other genetic variants and biological mechanisms that may affect breast cancer risk.  However, researchers acknowledge that other, unknown biological mechanisms related to IGF-1, which the study could not evaluate, may be involved.

The study was conducted using the UK Biobank Resource with support from the government of Canada through Genome Canada, the Canadian Institutes of Health Research, the Ministère de l'Économie, de la Science et de l'Innovation du Québec, and Genome Québec, as well as with grants from The National Institutes of Health, Cancer Research UK, and The European Union.

One or more authors reports support from the Wellcome Trust, Cancer Research UK, and/or the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre. The full list of disclosures can be found with the original article.

Ann Oncol. Published online March 11, 2020. Full text

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