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Interplay between c-Src and the APC/C co-activator Cdh1 regulates mammary tumorigenesis

Tao Han1, Shulong Jiang1,2,3, Hong Zheng4

  • 1Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.

Nature Communications
|August 18, 2019
PubMed

Insights

Cdh1 restrains breast cancer by suppressing c-Src kinase activity. Disrupting this feedback loop, through c-Src inhibition, restores Cdh1

Area of Science:

  • Cell Biology
  • Cancer Research
  • Molecular Oncology

Background:

  • The Anaphase Promoting Complex (APC) coactivator Cdh1 is crucial for cell cycle regulation and tumor suppression.
  • Mechanisms by which Cdh1 inhibits cancer progression and how cancer cells evade Cdh1's control are not fully understood.

Purpose of the Study:

  • To elucidate the role of Cdh1 in suppressing cancer progression.
  • To investigate the interplay between Cdh1 and the c-Src signaling pathway in breast cancer.

Main Methods:

  • Investigated the APC-independent function of Cdh1.
  • Utilized mouse models of breast cancer with Cdh1 depletion and PTEN loss.
  • Examined the effect of c-Src activity on APCCdh1 function via phosphorylation.
  • Assessed the impact of pharmacological c-Src inhibition on tumor suppressor activity.

Main Results:

  • Cdh1 suppresses c-Src kinase activity independently of the APC.
  • Cdh1 depletion accelerates breast cancer cell proliferation and tumor progression, especially when combined with PTEN loss.
  • Hyperactive c-Src phosphorylates Cdh1, inhibiting APCCdh1 ligase activity and disrupting Cdh1-APC complex formation.
  • Pharmacological inhibition of c-Src restores APCCdh1 tumor suppressor function against oncogenic substrates.

Conclusions:

  • A reciprocal feedback circuit exists between Cdh1 and c-Src, linking cell cycle control and c-Src signaling.
  • Targeting c-Src can restore the tumor-suppressive function of APCCdh1, offering a potential therapeutic strategy for breast cancer.

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