This research paper identifies a tumor-intrinsic mechanism driving resistance to endocrine therapy in luminal breast cancer. Researchers discovered that this resistance is associated with the upregulation of genes involved in cholesterol biosynthesis and the subsequent accumulation of the cholesterol metabolite 27-hydroxycholesterol (27HC) within tumor cells. This finding sheds light on a novel pathway contributing to how some breast cancers become unresponsive to standard treatments.
The study detailed that 27HC acts as an estrogen receptor (ER) agonist, promoting ER activation even in the absence of estradiol, and concurrently inhibits ER degradation. Utilizing cell lines and patient-derived xenografts (PDX) as preclinical models, the scientists demonstrated that this cholesterol metabolite significantly contributes to the observed resistance in endocrine-treated luminal breast cancer. Analysis of patient tumor data, including from the METABRIC cohort, further supported the clinical relevance of increased cholesterol pathway activity in tumors that had developed resistance.
Crucially, the researchers showed that inhibiting cholesterol synthesis, either through statins or squalene epoxidase inhibitors such as terbinafine, could restore sensitivity to endocrine therapy in these preclinical models. Combining endocrine therapy with squalene epoxidase inhibitors significantly reduced tumor growth in PDX models of endocrine-resistant luminal breast cancer. These findings propose that targeting cholesterol biosynthesis, specifically squalene epoxidase, represents a promising therapeutic strategy to overcome endocrine resistance in patients with this type of breast cancer.
