HDL also found to enhance cancer aggressiveness
Past studies have found cholesterol as an important regulator of breast cancer development. High-density lipoprotein (HDL) and its cellular receptor, 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.
Dr. Philippe Frank, PhD, Assistant Professor, Department of Biochemistry and Molecular Biology, at the Thomas Jefferson University and colleagues 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.
In order to examine the role HDL on cancer cells at the molecular level, the research team exposed breast cancer cell lines to HDL and noticed that signaling pathways involved in cancer progression were activated, and that the cells began to migrate in an experimental model mimicking metastasis.
Then the team limited the expression of the HDL receptor called SR-BI in the cells using silencing RNA to reduce the receptor’s levels. In response, the activities of the signaling pathways that promote tumor progression were reduced. In addition, cells with fewer SR-BI receptors displayed reduced proliferation rates and migratory abilities than cells with normal SR-BI levels. Most importantly, reduced SR-BI levels were associated with reduced tumor formation in a mouse model of tumorigenesis. After which the team blocked the SR-BI receptor in a breast cancer cell line with a drug called BLT-1 and noticed reduced proliferation and signaling via proteins linked to tumor formation.
Most importantly the team also demonstrated that pharmacological inhibition of SR-BI can weaken signaling and lead to decreased cellular proliferation in vitro.
The team writes “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.”
The researchers state in their conclusion “These results identify SR-BI as a potential target for the treatment of breast cancer.”
Dr. Frank comments "If we can block the activity of the HDL receptor in breast cancer, we may be able to limit the harmful effects of HDL, while maintaining levels that are beneficial for blood vessels.”
In closing he adds Additional studies will be needed to develop more specific drugs to inhibit SR-BI. "Also, we need to understand what levels of cholesterol are required by the tumor before trying to reduce or modify lipid levels in cancer patients.” “We hope this study will lead to the development of new drugs targeting SR-BI or cholesterol metabolism and eventually preventing tumor progression.”
This study appears in the journal Breast Cancer Research.