title: 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.
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 ΔNp63α, 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 ΔNp63α 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 ΔNp63α-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 ΔNp63α expression in quiescent MCF7 cells, where miR-205 was a downstream mediator. Furthermore, ΔNp63α-expressing MCF7 cells exhibited resistance to paclitaxel and doxorubicin. Expression of ΔNp63α 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 ΔNp63 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 ΔNp63α in induction of quiescence and downregulation of the BRCA1 pathway which suggested a role of ΔNp63α in the dormancy of luminal breast cancers.
authors.affiliation: Department of Project Programs, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Japan; Department of Pathology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Japan.
authors.forename: Ruhul
authors.initials: R
authors.lastname: Amin
authors.affiliation: Department of Project Programs, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Japan; Frontier Research Institute for Interdisciplinary Sciences (FRIS), Tohoku University, Sendai, Japan.
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Morita-Fujimura
authors.affiliation: Department of Project Programs, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tawarayama
authors.affiliation: Department of Life Science and Medical Bioscience, Waseda University, Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Semba
authors.affiliation: Department of Cancer Biology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Chiba
authors.affiliation: Department of Pathology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Fukumoto
authors.affiliation: Department of Project Programs, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Japan. Electronic address: sikawa@idac.tohoku.ac.jp.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Ikawa
mesh_terms: D019313:BRCA1 Protein / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D020033:Protein Isoforms; D011960:Receptors, Estrogen; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins
keywords: Breast cancer; Dormancy; Quiescence; Stem cell; p63