Inhibition of the RANK pathway significantly reduces recurrence and metastasis in breast cancer mouse models, according to the results of a recent study published in Cancer Research.
The study, “RANK signaling blockade reduces breast cancer recurrence by inducing tumor cell differentiation,” shows that RANK inhibition reduces cancer stem cells (CSC) in invasive tumors, impairing the start of metastasis, and enhances sensitivity to chemotherapy.
“Mortality in breast cancer is mainly due to survivor CSC after treatments, which are responsible for tumor recurrence and metastasis,” Dr. Eva Gonzalez-Suarez, the study’s lead author, said in a press release. “Previous studies of this and other research groups have shown that inhibition of RANK pathway may prevent breast cancer, but no one had proven the potential of RANK pathway inhibitors in the treatment of disease.”
In normal conditions, the RANK signaling pathway works to promote the development of the mammary gland in response to signals provided by sex hormones, such as progesterone. This usually happens in all women during their menstrual cycles and during pregnancy, but if the RANK signaling becomes disregulated, the mammary cells start reproducing rapidly when they are not supposed to, eventually leading to breast cancer.
Expression of RANK in human cancers is linked with reduced overall survival, but the therapeutic potential of RANK inhibitors once tumors have developed remained to be addressed.
In this study, Gonzalez-Suarez and her team used a breast cancer mouse model with high RANK expression and explored whether RANKL inhibitors could be used to prevent cancer progression.
The researchers found that “this inhibition does not reduce tumor growth, but promotes differentiation, reducing the population of CSC and impairing metastasis, which improves the prognosis,” suggesting that inhibition of the RANK/RANKL pathway could be potentially used as a new therapy in breast cancer.
Importantly, RANKL inhibitors, such as Prolia (denosumab), are already approved in the clinic and are indicated for the treatment of bone related diseases, osteoporosis, and bone metastasis, and thus may quickly become available for patients with advanced breast cancer.
“As these preclinical experiments suggest, and given that the RANKL / RANK pathway plays an important role in the development of primary breast cancer, inhibitors could serve as a potential target for the prevention and nonsurgical treatment of breast cancer,” Gonzalez-Suarez said.
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