Modulating apoptosis to revert pre-malignant breast organoids back to normal using novel small molecules

Treatment of patients diagnosed at early stage of Breast Cancer (BC) is a major medical challenge. To date, women diagnosed with pre-malignant condition as well as BRCA1/2 carriers are either monitored every few months or undergo prophylactic surgery. Both protocols bear the risk for undetected progression of the disease. We suggest a novel approach for BC prevention treatment.

ARTS is a pro-apoptotic protein which promotes apoptosis by binding to and inducing proteasome-mediated degradation of XIAP and Bcl-2. To examine the role of ARTS in breast cancer progression we have used the MCF10A 3D organoids. M1 cells represent normal epithelium, M2-pre-malignant and M3 are malignant breast cells. We have found that M2 pre-malignant cells exhibit an aberrant, non-functional form of ARTS. Silencing of ARTS alone in normal M1 organoids was sufficient to induce their transformation into a malignant phenotype both in vitro and in vivo. ARTS mimetic small molecules (AMs) promote activation of caspases by inducing degradation of both major anti-apoptotic proteins, XIAP and Bcl-2 in various cancer cell lines. Surprisingly, treatment of M2 pre-malignant organoids with AMs promoted the reversion of M2 pre-malignant organoids back into M1 normal phenotype. Our data suggest a new approach for prevention of breast cancer by treating early staged premalignant breast lesions, thereby avoiding the initiation and progression of breast cancer.