The estrogen receptor as a mediator of the pathological actions of cholesterol in breast cancer

Abstract

Despite increased survivorship among patients, breast cancer remains the most common cancer among women, and is the second leading cause of cancer death in women. The magnitude of this problem provides a strong impetus for new chemopreventative strategies and/or lifestyle changes that reduce cancer incidence. It is of significance, therefore, that several studies positively correlate obesity to the development of breast cancer. Importantly, obesity is also highly associated with elevated cholesterol, and cholesterol itself is a risk factor for breast cancer. Furthermore, patients taking statins demonstrate a lower breast cancer incidence, and decreased recurrence. The recent observation that 27-Hydroxycholesterol (27HC) is produced in a stoichiometric manner from cholesterol, together with our recent demonstration that it exerts partial agonist activity on both the estrogen and liver X receptors (ERs and LXRs), suggested a potential mechanistic link between hypercholesterolemia and breast cancer incidence. Using genetic and pharmacological approaches we have recently shown that elevation of circulating 27HC significantly increases tumor growth and metastasis in murine models of breast cancer. Further we have demonstrated in appropriate animal models that the impact of high fat diet on tumor pathogenesis can be mitigated by statins or by small molecule inhibitors of CYP27A1. These findings suggest that pharmacological or dietary modifications that lower total cholesterol, and by inference 27HC, are likely to reduce the impact of obesity/metabolic syndrome on breast cancer incidence.

Cholesterol reduces the sensitivity to platinum-based chemotherapy via upregulating ABCG2 in lung adenocarcinoma

“…More than half of elderly persons have elevated levels of blood cholesterol and triglyceride, which was not a serious problem for cancer in the past. But recently, several studies showed that cholesterol itself is a risk factor for cancer [16], and patients taking statins were found having a lower breast cancer incidence and decreased recurrence [17]. Moreover, cholesterol can activate substrate-stimulated ABCG2 ATPase activity and direct vesicular substrate transport [13].…”

Statins: a role in breast cancer therapy?

“…Hypercholesterolemia is an established clinical side effect of aromatase inhibitor (AI) therapy. Given the revelations about the estrogenic cholesterol metabolite 27HC, this phenomenon may counteract the intended effects of AIs . Breast cancer patients experiencing hypercholesterolemia during AI treatment may thus benefit from concomitant cholesterol‐lowering treatment to reduce the probability of 27HC‐driven ER actions.…”

“…oestradiol), it is likely to play a crucial role in hormone (oestrogen)‐dependent breast cancer. Importantly, 27HC, the oxysterol produced from cholesterol, is involved in the regulation of intracellular cholesterol homeostasis , but also acts as an endogenous selective oestrogen receptor modulator capable of increasing the growth and metastasis of tumours . Valuable clinical insight into the impact of statin treatment on 27HC in breast cancer patients was gained through collaboration with the McDonnell Lab at Duke University , where biological samples from our “window‐of‐opportunity” statin trial were analysed.…”

27-Hydroxycholesterol, an endogenous selective estrogen receptor modulator

“…It is important to keep in mind that the approximate IC 50 of 27HC for the ERs is 1μM [6]. 27HC is synthesized from cholesterol by CYP27A1, a mitochondrial P450 enzyme, which is primarily expressed in liver and cells of the myeloid immune lineage such as macrophages [40]. 27HC is metabolized by CYP7B1, another P450 enzyme that is expressed primarily in the brain, liver and other peripheral organs [41].…”