Abstract
Combined treatment with p53-activating drug APR-246 and a phosphatidylserine-targeting antibody, 2aG4, inhibits growth of human triple-negative breast cancer xenografts
Highlights
Triple-negative breast cancers (TNBC) constitute approximately 15-20% of all detected human breast cancers
APR-246 treatment for 24 or 48 hours significantly reduced the viability of both TNBC cell lines, with MDA-MB-468 cells being more sensitive to the drug (Figure 1A)
vascular endothelial growth factor (VEGF) is a potent angiogenic factor, as well as a survival factor, in breast cancer [38]. For this reason and because we found that APR246 lowered VEGF expression in xenograft tumors, we performed in vitro studies to determine whether APR-246 blocks production of VEGF by cultured MDA-MB-231 TNBC cells
Summary
Triple-negative breast cancers (TNBC) constitute approximately 15-20% of all detected human breast cancers. TNBC fail to express estrogen receptor; progesterone receptor; and Her-2-neu [1,2,3,4], the three molecules commonly targeted chemotherapeutically in hormone receptor-positive tumors. TNBC tumors frequently metastasize, leading to poor patient prognosis and death. It is important to develop better treatment strategies to reduce TNBC-related breast cancer mortality, since for patients with this aggressive type of cancer, the prognosis is not favorable following recurrence. The function of wildtype p53 tumor suppressor protein (wtp53) is to promote cell-cycle arrest and apoptosis and to inhibit vascular endothelial growth factor (VEGF)-dependent angiogenesis, which, if left unchecked, causes rapid tumor growth, metastasis, and mortality [6,7,8,9,10,11,12]. The majority of p53 mutations occur in the DNA-binding domain, which leads to aberrant regulation of p53 target genes involved in the aforementioned processes of apoptosis, cell-cycle arrest, and/or angiogenesis [13,14]
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