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Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
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Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells

Published on: February 21, 2014

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LYN-activating mutations mediate antiestrogen resistance in estrogen receptor-positive breast cancer

Luis J Schwarz, Emily M Fox, Justin M Balko

    The Journal of Clinical Investigation
    |November 18, 2014
    PubMed

    Insights

    Mutations in the LYN kinase, particularly in its SH2 domain, can drive resistance to antiestrogen therapies in estrogen receptor-positive breast cancer by increasing its activity.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Genetics

    Background:

    • Estrogen receptor-positive (ER(+)) breast cancers often develop resistance to antiestrogen therapies.
    • This resistance can manifest as continued tumor proliferation despite hormone deprivation.
    • SRC family kinases (SFKs) play roles in cellular signaling pathways relevant to cancer growth.

    Purpose of the Study:

    • To investigate the molecular mechanisms underlying resistance to antiestrogen therapy in ER(+) breast cancer.
    • To identify specific genetic alterations or signaling pathways involved in treatment escape.

    Main Methods:

    • Deep sequencing of ER(+) tumors resistant to letrozole.
    • Analysis of The Cancer Genome Atlas (TCGA) for LYN mutations.
    • RNA interference (RNAi)-based kinome screening in long-term estrogen-deprived (LTED) breast cancer cells.
    • Kinase assays and immunoblot analyses to assess LYN protein activity and phosphorylation.
    • Overexpression studies in breast cancer cell lines and xenograft models.

    Main Results:

    • A novel D189Y mutation in the inhibitory SH2 domain of the LYN kinase was identified in resistant ER(+) tumors.
    • LYN mutations were found in The Cancer Genome Atlas, and LYN was upregulated in LTED breast cancer cells.
    • The LYN(D189Y) mutation increased LYN kinase activity and reduced inhibitory phosphorylation, promoting resistance to antiestrogens and PI3K inhibitors.
    • LYN is essential for the growth of ER(+) LTED breast cancer cells.

    Conclusions:

    • Mutations in the LYN kinase, particularly within the SH2 domain, are implicated in mediating resistance to antiestrogen therapies in a subset of ER(+) breast cancers.
    • LYN kinase activity and its specific mutations represent potential therapeutic targets for overcoming treatment resistance.

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