Cholesterol is a waxy, fat-like substance found throughout the body, including the blood. High circulating cholesterol has emerged as an established breast cancer risk factor, although it is still not as well known as some other factors such as obesity. Tamoxifen works, in part, by reducing cholesterol. Now ongoing work presented at the AACR Special Conference on Tumor Immunology and Immunotherapy has demonstrated how high cholesterol promotes breast cancer metastasis.

Cholesterol and breast cancer

Breast cells have the propensity to accumulate cholesterol. Increases in circulating cholesterol have been shown to accelerate the development of mammary tumors and increase tumor aggressiveness in mouse models of breast cancer. For example, in one study, mice fed a high cholesterol diet (designed to approximate levels in a typical unhealthy diet) developed larger tumors that were faster growing and metastasized more easily compared to mice on a control diet.

High cholesterol is characterized by enhanced production of oxidized low-density lipoprotein, (LDL, the "bad" cholesterol). Oxidation occurs when LDL cholesterol reacts with free radicals. It has been demonstrated that normal breast cells readily internalize such oxidized LDL. The cells then respond to the presence of such LDL by increasing proliferative and pro-inflammatory signaling, thereby setting the stage for breast cancer development. However, note that high-density lipoprotein (HDL, the "good" cholesterol) has also been implicated in breast cancer risk and development.

Circulating cholesterol levels have also been observed to be reduced during mammary tumor development in mice, providing evidence of increased use of cholesterol by such tumors. In fact, low cholesterol is also associated with heightened breast cancer risk in women, possibly because undiagnosed tumors are already using cholesterol. Some researchers have theorized that breast cancer cells might migrate to seek out cholesterol by invasion when their needs are not being met in their local environment. This suggests that drastically reducing circulating cholesterol levels in the absence of other strategies to reduce metastasis could backfire.

Latest research shows how cholesterol can promote metastasis

The ongoing study referenced at the beginning of this news story was designed to investigate how cholesterol increases metastasis in an animal model of breast cancer. The tumor-promoting effects of cholesterol appear to require its conversion to 27-hydroxycholesterol (27HC) by the cytochrome P450 oxidase CYP27A1. In fact, 27HC is a primary metabolite of cholesterol. The authors previously reported that 27HC can help activate both the estrogen receptors (ERs) and liver X receptors (LXRs). This suggested a potential mechanism of action that could explain the apparent link between high cholesterol and breast cancer.

In the present study thus far, the authors have demonstrated that 27HC (1) increases tumor growth and lung metastases; (2) promotes an epithelial to mesenchymal-like transition (mesenchymal cells are able to develop into the tissues of the various tissues throughout the body); and (3) changes the metastatic microenvironment to promote colonization of cancer cells. The authors' ongoing work is designed to identify specific mechanisms by which 27HC causes these changes and thereby increases metastasis. The authors conclude that the data strongly indicates a role for 27HC in breast cancer pathophysiology and metastasis. The results provide new support for the study of possible chemopreventive benefits of cholesterol-reducing diets or drugs, as well as macrophage ablation strategies.

Please see our article on how to optimize your breast cancer diet for information on what to eat during all stages of treatment and recovery.