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, suggested a potential mechanistic link between hyper-cholesterolemia 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.

Keywords: 27-HYDROXYCHOLESTEROL; BREAST CANCER; CYP27A1; SERM; STATINS.

Figure 1. Cholesterol stimulates tumor growth in a mouse model of ER-positive breast cancer

The impact of hypercholesterolemia on breast cancer pathogenesis was evaluated in mice genetically engineered to express the PyMT oncogene in the mammary gland. In this well-validated model of ER-positive breast cancer tumors arise spontaneously. For this study mice were placed on either a control diet or a high cholesterol diet (2% cholesterol), ad libitum from weaning. At-5 weeks of age mice were ovariectomized and monitored for the appearance of the first palpable tumors, the growth of which was then recorded through time. (Figure adapted from Science 342: 1094-1098, 2013)

Figure 2. 27HC levels affect tumor growth in the MMTV-PyMT mouse model of breast cancer

The growth of tumors in the PyMT tumor model was evaluated in wild-type mice or in those which the enzyme responsible for (a) synthesis of 27HC from cholesterol (CYP27A1), or (b) metabolism of 27HC (CYP7B1) was genetically ablated. The complete details of this study have been published previously (29). (Figure adapted from Science 342: 1094-1098, 2013)