The growth hormone insulin-like growth factor-1 (IGF-1) is strongly implicated in the development of breast cancer, suggests research* published in the Annals of Oncology today.
Altering levels through diet, lifestyle or drugs may be an effective strategy for staving off the development of the disease, suggest the researchers.
Two analyses of information from several hundred thousand women enrolled in the UK Biobank study have shown for the first time that not only is there an association between higher levels of IGF-1 circulating in the blood and the development of breast cancer, but also that IGF-1 is likely to be a cause of the disease.
Researchers from the International Agency for Research on Cancer (IARC), Lyon, France, and the Cancer Epidemiology Unit at the University of Oxford, carried out two complementary studies to look at the role of IGF-1 in breast cancer development.
The first study looked at the associations between levels of IGF-1 in the blood and the chances of the disease developing in 206,263 women.
The second study used a technique called Mendelian randomisation to analyse data from 265 variants of genes (single nucleotide polymorphisms, or SNPs) known to be associated with IGF-1 levels in 122,977 cases of breast cancer and 105,974 women without cancer.
In this analysis, the researchers also looked at four SNPs for insulin-like growth factor-binding protein-3 (IGFBP-3), which may alter the availability of IGF-1.
Mendelian randomisation involves complex statistical analysis of data from large population studies, to enable researchers to rule out the influence of various factors that might otherwise make it harder to determine a possible cause.
Randomly inherited genetic variations that alter levels of IGF-1 and IGFBP-3 are unaffected by the disease process, so the researchers were able to use them to see whether people with a different genetic make-up had a different risk of breast cancer.
During an average of seven years of monitoring, 4360 cases of breast cancer occurred.
Among the 206,263 women included in the observational analysis, levels of IGF-1 ranged between an average of around 14 nmol/l of blood among those with levels in the lowest 20% and 29 nmol/l among those in the top 20%.
Women with IGF-1 levels in the top 20% had a 1.24-fold increased chance of developing breast cancer compared to those in the bottom 20%, after taking account of various influential factors, such as age, physical activity, weight (BMI), alcohol intake, smoking, educational attainment and other hormones and proteins in the blood, such as C-reactive protein and testosterone.
For every 1000 women who had the lowest IGF-1 levels, 21 were diagnosed with breast cancer over the study period, while 26 were diagnosed among those with the highest levels.
Every additional 5 nmol/l of IGF-1 was associated with a 1.11-fold increased risk. The results were consistent both for women who had and hadn’t gone through the menopause.
Results from the Mendelian randomisation study were similar. For every additional genetically predicted 5 nmol/l of IGF-1, the risk of breast cancer increased by 1.05.
But when the researchers looked at oestrogen receptor positive and negative breast cancers separately, IGF-1 was only associated with an increased risk of oestrogen receptor positive breast cancer. For every additional 5 nmol/l of IGF-1, the risk increased risk 1.06-fold.
Dr Neil Murphy, a scientist at IARC, said: “We found that higher levels of IGF-1 circulating in the blood, as determined by blood measurements and genetic markers, were related to higher breast cancer risk. These results support a probable causal role of the IGF pathway in breast cancer development.”
Dr Marc Gunter, scientist and head of the nutrition and metabolism section at IARC, said: “To our knowledge, this is largest single study and the first Mendelian randomisation study to examine the relationship between IGF-1 and breast cancer.
“Importantly, our Mendelian randomisation analyses yielded strikingly similar positive associations between IGF-1 and breast cancer as those found in our observational analyses.
“Taken together, these results provide the strongest evidence to date for a causal role of the IGF-pathway in breast cancer development, and 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. Our next step is to gain a fuller understanding of which lifestyle practices can alter IGF-1 concentrations and, in turn, the chances of breast cancer developing.”
Dr Anika Knüppel, a nutritional epidemiologist at the University of Oxford, 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 randomisation in our study leads the way for research into how the IGF-1 pathway can be harnessed in breast cancer prevention.”
Dr Murphy added: “Although levels of IGF-1 in the blood are potentially modifiable it is currently unknown how long an intervention aimed at altering IGF-1 concentrations would have to be applied in order to have a measurable effect or whether there could be other adverse impacts of such an intervention.”
*Murphy N, et al. Insulin-like growth factor-1 (IGF-1), insulin growth factor-binding protein-3 (IGFBP-3) and breast cancer risk: observational and Mendelian randomization analyses with ~ 430,000 women. Annals of Oncology doi:10.1016/j.annonc.2020.01.066