Hypercholesterolemia promotes the intravasation of breast tumor cells through an LDL-LDLR axis

Majority of metastasis in breast cancer occur via the dissemination of tumor cells through the bloodstream. How tumor cells enter the blood (intravasation) is, however, a poorly understood mechanism at the cellular and molecular levels. Particularly uncharacterized is how intravasation is affected by systemic factors. High levels of systemic LDL-cholesterol have been shown to contribute to breast cancer progression and metastasis in various models, but the mechanisms involved are still undisclosed. Here we show that a high cholesterol diet promotes intravasation in two mouse models of breast cancer and that this could be reverted by blocking LDL binding to LDLR in tumor cells. Moreover, we show that LDL promotes vascular invasion in vitro and a phenotypic change resembling VM, and augments the expression of Serpine2, previously shown to be required for both VM and intravasation. Finally, we show that blocking the binding of LDL to LDLR on tumor cells prevents the increase in lung metastasis promoted by a high cholesterol diet. Overall, our manuscript unravels novel mechanisms by which systemic hypercholesterolemia may affect the onset of metastatic breast cancer by favoring phenotypic changes in breast cancer cells and increasing intravasation.