Sensitizing Triple Negative Breast Cancer to Chemotherapy by Mutant-p53-Rescue Drugs.

Triple negative breast cancer (TNBC) refers to a subtype of particularly aggressive breast cancer that is negative for expression of estrogen receptor and progesterone receptor and lacks HER2 overexpression. This subtype accounts for approximately 15% of all types of breast cancer and is much more prevalent among African-American women who are premenopausal. Due to lack of sufficient targets, patients with TNBC are not candidates for endocrine therapy or targeted therapy against HER2. Chemotherapy is the primary choice of systemic therapy for this disease. Although responsive to chemotherapy, TNBC is associated with more rapid relapse following therapy, increased prevalence of distant metastases, and shorter survival compared with other subtypes of breast cancer. Therefore, there is an urgent need to develop effective and mechanism-driven strategies to increase the efficacy of chemotherapy and overcome drug resistance for managing this aggressive disease.The vast majority of TNBCs express a mutant p53. Mounting evidence has suggested an association between failure of p53 signaling and resistance of tumors to chemotherapy, particularly to DNA-damaging chemotherapy, including anthracyclines. Unlike wild-type p53, mutant p53 is normally accumulated at high levels in tumors due to impaired p53 degradation. Rational design of combination therapies directed toward restoring p53 function to the highly accumulated mutant p53 should offer substantial benefit in improving the outcome of chemotherapy for TNBC where p53 is prevalently mutated.The present study was designed to investigate the potential of using a mutant-p53-rescue small molecule, PRIMA-1, and selenium (in the form of methylseleninic acid, MSA) to increase the efficacy of doxorubicin (a prototype compound for anthracyclines) in TNBCs through restoring p53 signaling. PRIMA-1 has been demonstrated to induce mutant p53-dependent cell death by restoring wild-type conformation to mutant p53 and thereby p53 trans-activation . Selenium is a low-cost and low-toxicity micronutrient. Previous research has shown the ability of selenium to induce p53 redox modification, which could potentially lead to at least partial restoration of p53 function to mutant p53. We show that both PRIMA-1 and selenium could greatly increase the growth-inhibitory potency of doxorubicin in TNBC cell lines (MDA-MB-231, MDA-MB-468, BT-549 and HCC70) expressing a mutant p53. The combinatory action of PRIMA-1 and doxorubicin or selenium and doxorubicin is synergistic. Combination treatments result in significantly enhanced induction of apoptosis and p21 expression than either agent alone. Knockdown of p21 attenuates apoptosis induction by the combination treatments. More importantly, the combinatory efficacies are mutant-p53 dependent since knocking down p53 negates combination treatment-induced apoptosis and p21 expression. The data therefore indicate that using PRIMA-1 or selenium to restore, at least partially, the wild-type function to mutant p53, could represent a highly effective approach to increase the efficacy of doxorubicin for the treatment of TNBCs. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6105.