Body composition and breast cancer risk: is the association mediated by immune function and chronic inflammation?

  • Topic: Breast cancer
  • Institution: International Agency for Research on Cancer (IARC)
  • Country: France
  • Status: Ongoing

Co-applicant/s

Dr Sabina Rinaldi, International Agency for Research on Cancer, France
Dr Isabelle Romieu, National Institute of Public Health, Mexico

Scientific abstract

(View plain language abstract)

Background

Breast cancer (BC) is a major public health problem, as it is the most common cancer in women from Westernised countries, and its incidence is increasing steadily in low and middle-income countries. Obesity and physical inactivity are important risk factors for post-menopausal BC, but the aetiology of pre-menopausal BC is still largely unknown.

Obesity involves many metabolic changes, but so far little is known about the specific metabolic alterations and dysfunctions linking obesity to cancer. Evidence is accumulating that energy balance, excess weight, obesity and physical inactivity are associated with immune response and chronic inflammation that therefore could mediate obesity related cancer risk. In solid tumours, Th1 cytokines have been associated with antitumor immune responses and recent experimental studies showed that IFN-gamma and TNF-alpha can control tumour development. Inflammation could be implicated in the development of up to 20% of all human cancers and chronic inflammatory diseases or infections are strong risk factors for certain cancers.

Regarding BC, in vivo studies have shown that breast tumour-associated leukocytes release pro-inflammatory cytokines that activate immune response and enhance tumour promotion. Very few prospective studies have been conducted so far on breast cancer risk in relation to inflammation markers other than C-reactive protein (CRP), and in particular on cytokines related to immune response.

Hypothesis and objectives

We propose to address the hypothesis that factors involved with immune function and low-grade inflammatory states are related to BC risk. The objective of the project will be to examine if elevated blood concentrations of Th1 and Th2 cytokines as well as adipokines are associated with breast cancer risk, overall and by breast cancer subtypes. In addition, we will examine and quantify the relationships of these biomarkers with variable degrees of adiposity and physical activity, and with serum levels of other metabolic markers. Ultimately, we will develop a comprehensive multivariate metabolic risk score for BC.

Settings and methods

The proposed study will be nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), an ongoing prospective study investigating risk factors for cancer and other chronic diseases. We will select 1500 breast cancer cases and 1500 matched controls from EPIC. Measurements of Th1 and Th2 cytokines and adipokines will be performed using commercially available immunoassays. Conditional logistic regression will be used to estimate relative risks of BC by level of each of the biomarkers as well as with levels of anthropometric and physical activity measures, adjusting for inflammatory /immune markers and other metabolic markers (mediation analyses). Factorial analyses will be used to construct scores of metabolic markers.

Impact

This set of data may shed light on the biochemical pathways linking adiposity and BC risk in pre- and post-menopausal women, and would help disentangle this association by receptor status of the tumour. The findings arising from this research project will contribute to increase the available knowledge regarding the association between excess weight and obesity and BC risk, and should help clarifying the mechanisms underlying this relationship. In terms of prevention, our results should give support to the reduction of chronic inflammation caused by obesity.

Plain language abstract

Background

Breast cancer is a major public health problem, as it is the most common cancer in women from Westernised countries, and its incidence is increasing steadily in low and middle income countries. Obesity and physical inactivity are important risk factors for post-menopausal breast cancer, but factors associated with breast cancer before menopause are still largely unknown.

Obesity involves many metabolic changes, but so far little is known about the mechanisms linking obesity to cancer. Evidence is accumulating that excess weight, obesity and physical inactivity are associated with immune response and chronic inflammation that therefore could explain part of the association between obesity and cancer.

Aims and objectives

We hypothesised that blood levels of markers of inflammation and immune response may explain the relationships of breast cancer risk with nutritional lifestyle factors.

How will it be done

We propose to address this hypothesis by measuring inflammatory factors in pre-diagnostic blood samples from women who subsequently had a clinical diagnosis of breast cancer, and from women of comparable age who did not develop cancer, within the European EPIC cohort.

Potential impact

This set of data may shed light on the biochemical pathways linking adiposity and breast cancer risk before and after menopause, as well as according to subtypes of breast cancer. The findings arising from this research project will contribute to increase the available knowledge regarding the association between excess weight and obesity and breast cancer risk, and should help clarifying the mechanisms underlying this relationship. In terms of prevention, our results should give support to the reduction of chronic inflammation caused by obesity.