Novel roles of la,25(OH)2D3 on DNA repair provide new strategies for breast cancer treatment

摘要

Breast cancers classified as triple-negative (TNBC) and BRCA1 -deficient, are particularly aggressive and difficult to treat. A major breakthrough was the finding that these tumors are exquisitely sensitive to inhibitors of poly(ADP-ribose) polymerase (PARPi). Phase II clinical trials have shown encouraging outcomes, with tolerable side effects. However, a significant fraction of these cancers acquire resistance. Elegant studies demonstrated that loss of the DNA repair protein 53BP1 contributes to the resistance of BRCA1-deficient cells and tumors to PARPi. Thus, raising the levels of 53BP1 in these aggressive tumors could potentially restore their sensitivity to PARPi and other genotoxic agents. We will review here our studies revealing that la,25(OH)2D3, an active form of vitamin D, stabilizes 53BP1 levels in tumor cells. Breast tumor cells that become BRCA1-deficient activate cathepsin L-mediated degradation of 53BP1 to ensure genome stability and proliferation. Importantly, la,25(OH)2D3 treatment restores the levels of 53BP1 as efficiently as cathepsin L inhibitors, which results in increased genomic instability in response to PARPi or radiation, and reduced proliferation. Furthermore, analysis of human breast tumors identified nuclear cathepsin L as a positive biomarker for TNBC, which correlates inversely with 53BP1 when vitamin D receptor (VDR) nuclear levels are low. The major findings of these studies are: (1) identification of a new pathway contributing to breast cancers with the poorest prognosis; (2) discovery of the ability of la,25(OH)2D3 to inhibit this pathway; and (3) discovery of a triple biomarker signature for identification of patients that could benefit from the treatment.