Having High cholesterol levels is already known to have negative effects on the body. A recently published Duke University study showed that high cholesterol levels increase the risk of breast cancer and metastases. At a time when immunotherapy offers new ways to treat cancer, this work offers new therapeutic perspectives.
Breast cancer is the leading cause of cancer death in women in the US. Almost 11% of postmenopausal cancers are due to overweight and obesity. In addition, 20-30% of patients with these types of cancers will develop metastases, although this leads to the death of most cancer cells.
An alternative cell death pathway: ferroptosis
When talking about the programmed physiological death of cells in the body, the first term that comes to mind is apoptosis. But there are other alternative mechanisms, and since 2012 another form of cell death has been identified, ferroptosis. This necrotic cell death process is caused by free iron in the body and the occurrence of massive lipid peroxidation (oxidative stress). This leads to a change in the redox metabolism and membrane permeability of the cell, resulting in cell death. In cancer, metastasis requires cells to increase their uptake of exogenous lipids, causing oxidative stress and thus exposing them to cell death by ferroptosis.
A population of cancer cells protected from oxidative stress
Following the observation that high cholesterol levels are a risk factor for breast cancer and lead to worse outcomes in women who have developed the disease, researchers at Duke University set up a study by growing cancer cell lines (breast cancer and melanoma) in vitro.
By exposing them to 27HC, a circulating metabolite of cholesterol, they demonstrated the selection of a specific subpopulation of cells. These specific cells showed a high activity of the GPX4 enzyme, which is involved in the synthesis of glutathione, a natural protector against oxidative stress.
In addition, the presence of a 27HC receptor would increase their tumorigenic and metastatic capabilities. These cells, derived from the primary tumor, could then detach from the extracellular matrix and spread without undergoing the mechanisms associated with ferroptosis.
The therapeutic implications of this work are multiple and several avenues are being explored, either by reducing the consequences of hypercholesterolemia through appropriate treatment or by blocking the conversion of cholesterol to 27HC. Furthermore, playing a central role in ferroptosis resistance, GPX4 could become a relevant candidate for the treatment of cancer diseases, and several GPX4 inhibitors are currently under investigation.