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DEAR1 is a dominant regulator of acinar morphogenesis and an independent predictor of local recurrence-free survival in early-onset breast cancer.

Steven T Lott1, Nanyue Chen, Dawn S Chandler

  • 1Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

Plos Medicine
|June 19, 2009

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View abstract on PubMed

Summary

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  • Biomedical And Clinical Sciences
  • Oncology And Carcinogenesis
  • Predictive And Prognostic Markers
  • Dear1 Is A Dominant Regulator Of Acinar Morphogenesis And An Independent Predictor Of Local Recurrence-free Survival In Early-onset Breast Cancer.
    • This summary is machine-generated.

    A novel gene, DEAR1 (ductal epithelium-associated RING Chromosome 1), is implicated in aggressive early-onset breast cancer. Loss of DEAR1 expression predicts recurrence and is linked to poor prognosis in young women.

    Area of Science:

    • Genetics and Molecular Biology
    • Oncology
    • Cell Biology

    Background:

    • Early-onset breast cancer often presents aggressively with higher recurrence rates.
    • Genetic pathways underlying early-onset breast cancer remain largely unknown.
    • DEAR1 (ductal epithelium-associated RING Chromosome 1) is a novel TRIM-family gene.

    Purpose of the Study:

    • To identify novel genes involved in early-onset breast cancer.
    • To investigate the role of DEAR1 in mammary gland morphogenesis.
    • To assess DEAR1 as a prognostic marker for early-onset breast cancer.

    Main Methods:

    • Suppression subtractive hybridization to identify DEAR1.
    • Analysis of DEAR1 expression, mutations, and deletions in breast cancer cell lines and tumors.
    • Functional studies using 3D basement membrane culture and knockdown experiments.
    • Immunohistochemical analysis of DEAR1 expression in patient cohorts.

    Main Results:

    • DEAR1 maps to a region of frequent loss of heterozygosity (Chromosome 1p35.1).
    • DEAR1 is downregulated in ductal carcinoma in situ and mutated/deleted in breast cancers.
    • Restoration of DEAR1 initiated acinar morphogenesis and restored tissue architecture.
    • DEAR1 knockdown disrupted tissue architecture, polarity, and lumen formation.
    • DEAR1 expression is an independent predictor of local recurrence-free survival in young women.
    • DEAR1 expression correlates with family history and triple-negative breast cancer phenotype.

    Conclusions:

    • DEAR1 is genetically altered and downregulated in breast cancer.
    • DEAR1 plays a critical role in regulating mammary gland acinar morphogenesis.
    • DEAR1 expression is a potential prognostic marker for stratifying early-onset breast cancer risk.

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