Breast cancer is the most commonly occurring cancer in women in Western societies. 1 It is estimated that 207,090 new cases will be diagnosed and that in the United States, 39,840 women will die of the disease in 2010 (American Cancer Society, Cancer Facts & Figures 2010, http://www. cancer.org/Research/cancer-facts-and-figures-2010, last accessed November 15, 2010. Interestingly, the incidence is about 5 times higher in Western countries than in developing countries. 2 Moreover, relocation and migrational studies have demonstrated that migration from a region with low incidence to a region with high incidence increases breast cancer incidence in the immigrant population. 3 These observations suggest a strong environmental influence on breast cancer development.Diet and obesity are now considered important risk factors for cancer development. 4,5 However, despite major modifications of its metabolism during obesity development and its function in tissue pathogenesis, little is known about the metabolism and role of plasma cholesterol in cancer development. Epidemiological studies have demonstrated that patients with cancer have abnormal levels of high-density lipoprotein (HDL)-cholesterol and low-density lipoprotein (LDL)-cholesterol, 6,7 which are the major lipoprotein carriers of cholesterol in human plasma. In addition, numerous studies have established that transformed cells and tumors exhibit abnormal regulation of several genes that are under the control of cholesterol. The products of these genes include the LDL receptor (LDL-R), hydroxy-methyl-glutaryl coenzyme A reductase (HMG-CoA Reductase), and their regulators, the sterol regulatory element binding proteins. 8 -13 As a consequence, these genes are dysregulated at the transcriptional level during tumorigenesis. These data suggest that transformed cells may require or utilize more cholesterol than normal cells, and this may be associated with their increased rate of proliferation. More recent studies have implicated HDL during tumor formation in breast cancer. 14 -16 However, their precise function remains controversial. The present study was performed to test the hypothesis that dietary cholesterol and plasma cholesterol levels have an important role in the regulation of breast cancer onset and progression.

IntroductionPrevious studies have identified cholesterol as an important regulator of breast cancer development. High-density lipoprotein (HDL) and its cellular receptor, the scavenger receptor class B type I (SR-BI) have both been implicated in the regulation of cellular cholesterol homeostasis, but their functions in cancer remain to be established.MethodsIn the present study, we have examined the role of HDL and SR-BI in the regulation of cellular signaling pathways in breast cancer cell lines and in the development of tumor in a mouse xenograft model.ResultsOur data show that HDL is capable of stimulating migration and can activate signal transduction pathways in the two human breast cancer cell lines, MDA-MB-231 and MCF7. Furthermore, we also show that knockdown of the HDL receptor, SR-BI, attenuates HDL-induced activation of the phosphatidylinositol 3-kinase (PI3K)/protein Kinase B (Akt) pathway in both cell lines. Additional investigations show that inhibition of the PI3K pathway, but not that of the mitogen-activated protein kinase (MAPK) pathway, could lead to a reduction in cellular proliferation in the absence of SR-BI. Importantly, whereas the knockdown of SR-BI led to decreased proliferation and migration in vitro, it also led to a significant reduction in tumor growth in vivo. Most important, we also show that pharmacological inhibition of SR-BI can attenuate signaling and lead to decreased cellular proliferation in vitro. Taken together, our data indicate that both cholesteryl ester entry via HDL-SR-BI and Akt signaling play an essential role in the regulation of cellular proliferation and migration, and, eventually, tumor growth.ConclusionsThese results identify SR-BI as a potential target for the treatment of breast cancer.

It is becoming increasingly apparent that the tumor microenvironment plays a critical role in human breast cancer onset and progression. Therefore, we isolated cancer-associated fibroblasts (CAFs) from human breast cancer lesions and studied their properties, as compared with normal mammary fibroblasts (NFs) isolated from the same patient. Here, we demonstrate that 8 out of 11 CAFs show dramatic downregulation of caveolin-1 (Cav-1) protein expression; Cav-1 is a well-established marker that is normally decreased during the oncogenic transformation of fibroblasts. Next, we performed gene expression profiling studies (DNA microarray) and established a CAF gene expression signature. Interestingly, the expression signature associated with CAFs encompasses a large number of genes that are regulated via the RB-pathway. The CAF gene signature is also predictive of poor clinical outcome in breast cancer patients that were treated with tamoxifen mono-therapy, indicating that CAFs may be useful for predicting the response to hormonal therapy. Finally, we show that replacement of Cav-1 expression in CAFs (using a cell-permeable peptide approach) is sufficient to revert their hyper-proliferative phenotype and prevent RB hyper-phosphorylation. Taken together, these studies highlight the critical role of Cav-1 downregulation in maintaining the abnormal phenotype of human breast cancer-associated fibroblasts.