Defining the role of diet and age in the spreading of breast cancer

This research assesses metabolism, gene and protein expression in breast cancer cells, aged, obese and control mice with breast tumours and patient samples to understand formation of metastasis.

• Topic: Breast cancer
• Institution: VIB-Flemish Institute for Biotechnology
• Country: Belgium
• Status: Ongoing

Researcher: Sarah-Maria Fendt

Grant title: Defining the role of diet and age in metastasis formation

The physiology of patients influences cancer progression, however why this is the case remains largely elusive. With this funding we aim to mechanistically understand how alterations in whole body physiology contribute to cancer metastasis. – Prof Sarah-Maria Fendt

Background

Breast cancer is the most prevalent cancer and ~99% of cases occur in women. Unfortunately, ~25% of breast cancer patients die due to the spread of cancer cells to distant organs, which is called metastasis formation. This progression of breast cancer results in over 685,000 deaths each year worldwide.

At the same time, there is a rising trend of obesity, which is a known risk factor for breast cancer progression and mortality. Worldwide, 1 billion adult women are overweight and 350 million are obese (WHO data). Moreover, elderly patients (>60 years) have a significantly poorer prognosis at the metastatic stage and about 50% of breast cancer cases are diagnosed in elderly women.

Both risk factors, age and obesity, result in a shifted body composition with more fat percentage. Yet, we do not know the mechanism by which body fat, increased by diet-induced obesity or ageing, contributes to metastasis formation.

Aims and objectives

We have found that the fat component palmitate is increased in obese and aged mice. Moreover, we discovered that the breakdown of this palmitate in cancer cells promotes metastasis formation in lungs. Yet, we do not know how palmitate increases in the lung and why only palmitate, but not any other fat components, induces lung metastasis.

Therefore, we will:

1. determine the mechanism by which palmitate specifically induces lung metastasis formation. We hypothesise that palmitate attaches to proteins (which is called palmitoylation) and that this modification of proteins allows palmitate to induce lung metastasis formation.
2. define how fat availability increases in lungs. We hypothesise that lung cells respond to high fat diet by releasing palmitate to the lung environment.
3. identify how ageing alters the metabolism within the lung metastasis. We hypothesise that metastases arising in aged animals have an altered fat metabolism compared with metastases arising in young animals.

How it will be done

In this research, we will assess the metabolism, gene and protein expression with spatial and single cell resolution in breast cancer cells, aged or obese and control mice with breast tumors that spontaneously metastasise and samples from breast cancer patients.

Potential impact

Metastasis formation is the major cause of death in breast cancer patients and has surpassed in women the mortality resulting from lung cancer. Major risk factors for developing or dying of metastases are obesity and age. Yet most pre-clinical studies, defining cancer mechanisms, are conducted in young and lean mice. Thus, we largely lack an understanding of how diet-induced obesity and ageing contribute to breast cancer progression. With this project, we will close this gap and specifically assess this relationship between cancer and fat.