?Np63? 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.

ABSTRACT: Despite apparent resection of tumors, breast cancer patients often suffer relapse due to remnant dormant tumor cells. Although quiescence of cancer stem cells is thought as one of the mechanisms regulating dormancy, the mechanism underlying quiescence is unclear. Since ?Np63?, 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 ?Np63? 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 ?Np63?-dependent induction of quiescence and acquisition of stemness in MCF7. More interestingly, through Ingenuity Pathway analysis, we found for the first time that BRCA1 pathway was the most significantly downregulated pathway by ?Np63? expression in quiescent MCF7 cells, where miR-205 was a downstream mediator. Furthermore, ?Np63?-expressing MCF7 cells exhibited resistance to paclitaxel and doxorubicin. Expression of ?Np63? in normal MCF10A basal cells increased proliferation and stemness, but did not affect more aggressive luminal (T47D) and basal (MDA-MB-231) cells with p53 mutation. Gene expression datasets analyses suggested that ?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 ?Np63? in induction of quiescence and downregulation of the BRCA1 pathway which suggested a role of ?Np63? in the dormancy of luminal breast cancers.

SUBMITTER: Amin R 

PROVIDER: S-EPMC5423149 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature