Osteoporosis drug, Zoledronic acid found effective in breast cancer: Study
An aggressive form of breast cancer can now be treated with zoledronic acid (ZA), a drug used for the treatment of osteoporosis suggests a study published in the Journal of Experimental Medicine. The drug works by inhibiting an enzyme called UGT8, the same enzyme is responsible for the progression of basal-like breast cancer (BLBC).
BLBC is a particularly aggressive form of breast cancer that typically affects younger, premenopausal women. It is hard to treat because the tumor cells are usually "triple negative," lacking the estrogen receptor, progesterone receptor, and HER2 protein that are the main therapeutic targets for other forms of breast cancer. As a result, the prognosis for patients with BLBC is worse than any other subtype of this cancer.
UGT8 catalyzes the first step in the synthesis of sulfatide, a type of lipid that is found on the surface of cells and has been implicated in cancer progression. Depleting UGT8 from these cells lowered sulfatide levels and reduced the cells' ability to form tumors when injected into mice.
The study was conducted by professor Chenfang Dong from the Zhejiang University School of Medicine in Hangzhou, China, and colleagues, to find the metabolic determinants contributing to the aggressiveness of BLBC.
"The highly aggressive nature and the absence of effective therapeutics for basal-like breast cancer make it a high priority to elucidate what determines its aggressiveness and identify potential therapeutic targets," says Professor Dong.
Cancer cells must alter their metabolism for their survival and metastasis. For the study, the researchers of China examined over 5,000 breast cancer patient samples.
Based on the study, following inferences were drawn:
- UGT8 expression is up-regulated in BLBC subtype
- UGT8 positively correlates with Sox10 and is a direct target of Sox10
- UGT8 expression activates the sulfatide biosynthetic pathway and enhances breast cancer cell migration and invasion
- ZA is a direct inhibitor of UGT8 and suppresses the sulfatide biosynthetic pathway and breast cancer cell migration and invasion
- UGT8 activates αVβ5 signaling via up-regulating sulfatide
- UGT8 promotes tumorigenicity of breast cancer
- Inhibition of UGT8 by shRNA or ZA suppresses metastasis of breast cancer
Zoledronic acid is a drug that is approved to treat a variety of bone diseases, including osteoporosis, and is on the World Health Organization's list of safe and effective medicines essential for global health. Dong and colleagues confirmed that zoledronic acid is a direct inhibitor of UGT8 that reduces the levels of sulfatide in basal-like breast cancer cells. Treatment with the drug impaired the cells' ability to invade their surroundings and, accordingly, prevented them from metastasizing to the lungs after they were injected into the mice.
"UGT8 is a potential prognostic indicator and druggable target of BLBC and that pharmacologic inhibition of UGT8 by ZA offers a promising opportunity for treating this challenging disease," concluded the authors.