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Using Mouse Mammary Tumor Cells to Teach Core Biology Concepts: A Simple Lab Module
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Phorbol ester dramatically increases incidence of methotrexate-resistant mouse cells: possible mechanisms and

A Varshavsky

    Cell
    |August 1, 1981
    PubMed

    Insights

    Tumor promoters like 12-O-tetradecanoyl-phorbol-13-acetate (TPA) can increase gene amplification. TPA significantly enhances the incidence of methotrexate resistance in 3T6 cells by promoting dihydrofolate reductase (DHFR) gene amplification.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Genetics

    Background:

    • Tumor promoters are agents that can enhance cancer development.
    • Gene amplification is a known mechanism in cancer progression.
    • The role of tumor promoters in facilitating gene amplification is not fully understood.

    Purpose of the Study:

    • To investigate the hypothesis that tumor promoters may facilitate gene amplification.
    • To determine if 12-O-tetradecanoyl-phorbol-13-acetate (TPA) influences gene amplification.
    • To quantify the effect of TPA on methotrexate resistance in 3T6 cells.

    Main Methods:

    • Single-step selection for methotrexate resistance in 3T6 cells.
    • Comparison of resistant cell incidence with and without TPA exposure.
    • Quantification of dihydrofolate reductase (DHFR) gene copy numbers in resistant clones.

    Main Results:

    • TPA increased the incidence of methotrexate-resistant 3T6 cells up to 100-fold.
    • The TPA effect was observed when added simultaneously with methotrexate.
    • DHFR gene copy numbers were significantly elevated in resistant clones, correlating with methotrexate concentration, independent of TPA presence during selection.

    Conclusions:

    • 12-O-tetradecanoyl-phorbol-13-acetate (TPA) acts as a potent enhancer of gene amplification.
    • TPA significantly increases the frequency of drug-resistant cells through gene amplification.
    • These findings suggest a mechanism by which tumor promoters contribute to cancer progression via gene amplification.

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