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

Ruhul Amin, Yuiko Morita-Fujimura, Hiroshi Tawarayama, Kentaro Senba, Natsuko Chiba, Manabu Fukumoto, Shuntaro Ikawa

    Research output: Contribution to journalArticle

    12 Citations (Scopus)

    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.

    Original languageEnglish
    JournalMolecular Oncology
    DOIs
    Publication statusAccepted/In press - 2015 Sep 22

    Fingerprint

    Estrogen Receptors
    Down-Regulation
    Breast Neoplasms
    Cell Line
    MCF-7 Cells
    Breast
    Recurrence
    Bone Morphogenetic Proteins
    Neoplastic Stem Cells
    Microarray Analysis
    Paclitaxel
    MicroRNAs
    Doxorubicin
    Neoplasms
    Protein Isoforms
    Stem Cells
    Epithelium
    Maintenance
    Cell Proliferation
    Gene Expression

    Keywords

    • Breast cancer
    • Dormancy
    • P63
    • Quiescence
    • Stem cell

    ASJC Scopus subject areas

    • Cancer Research
    • Genetics
    • Molecular Medicine

    Cite this

    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. / Amin, Ruhul; Morita-Fujimura, Yuiko; Tawarayama, Hiroshi; Senba, Kentaro; Chiba, Natsuko; Fukumoto, Manabu; Ikawa, Shuntaro.

    In: Molecular Oncology, 22.09.2015.

    Research output: Contribution to journalArticle

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    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.",
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    AU - Tawarayama, Hiroshi

    AU - Senba, Kentaro

    AU - Chiba, Natsuko

    AU - Fukumoto, Manabu

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