ΔNp63α induces quiescence and downregulates the BRCA1 pathway in estrogen receptor-positive luminal breast cancer cell line MCF7 but not in other breast cancer cell lines

Despite apparent resection of tumors, breast cancer patients often suffer relapse due to remnant dormant tumor cells. Although quiescence of cancer stern cells is thought as one of the mechanisms regulating dormancy, the mechanism underlying quiescence is unclear. Since Delta Np63 alpha, an isoform of p51/p63, is crucial in the maintenance of stem cells within mammary epithelium, we investigated its roles in the regulation of dormancy in normal and malignant breast cells. Inducible expression of Delta Np63 alpha in MCF7 estrogen receptor positive (ER+) luminal breast cancer cells led to quiescence and acquisition of progenitor-like properties. Judging from mRNA-microRNA microarray analysis, activation of bone morphogenetic protein (BMP) signaling and inhibition of Wnt signaling emerged as prominent mechanisms underlying Delta Np63 alpha-dependent induction of quiescence and acquisition of sternness in MCF7. More interestingly, through Ingenuity Pathway analysis, we found for the first time that BRCA1 pathway was the most significantly downregulated pathway by Delta Np63 alpha expression in quiescent MCF7 cells, where miR-205 was a downstream mediator. Furthermore, Delta Np63 alpha-expressing MCF7 cells exhibited resistance to paclitaxel and doxorubicin. Expression of Delta Np63 alpha in normal MCF10A basal cells increased proliferation and sternness, but did not affect more aggressive luminal (T47D) and basal (MDA-MB-231) cells with p53 mutation. Gene expression datasets analyses suggested that Delta Np63 expression is associated with relapse-free survival of luminal A/B-type patients, but not of the other subtypes. Our results established a cell type-specific function of Delta Np63 alpha in induction of quiescence and downregulation of the BRCA1 pathway which suggested a role of Delta Np63 alpha in the dormancy of luminal breast cancers. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.