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Adaptor SH3BGRL promotes breast cancer metastasis through PFN1 degradation by translational STUB1 upregulation

Shaoyang Zhang1,2, Xuemin Guo3,4, Xiufeng Liu1

  • 1Translational Medicine Centre, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Oncogene
|July 31, 2021
PubMed

Insights

SH3BGRL protein promotes breast cancer metastasis by reducing PFN1 levels, leading to poor prognosis. Restoring PFN1 can counteract this effect, suggesting SH3BGRL as a therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Metastatic recurrence remains a significant challenge in breast cancer treatment.
  • The molecular mechanisms driving breast cancer metastasis are not fully understood.

Purpose of the Study:

  • To investigate the role of SH3BGRL protein in breast cancer progression and metastasis.
  • To elucidate the underlying molecular mechanisms of SH3BGRL-mediated metastasis.
  • To evaluate SH3BGRL as a prognostic marker and therapeutic target for breast cancer.

Main Methods:

  • Analysis of SH3BGRL expression in breast cancer patient tissues.
  • In vivo studies using nude mice to assess tumorigenicity, migration, invasiveness, and lung colonization.
  • Investigation of molecular interactions involving SH3BGRL, PFN1, STUB1, and ribosomal proteins.
  • Assessment of downstream signaling pathways including AKT, NF-kB, and WNT.
  • Correlation analysis of clinical data with molecular findings.

Main Results:

  • SH3BGRL is upregulated in breast cancer patients, particularly those with metastatic relapse, indicating poor prognosis.
  • SH3BGRL promotes breast cancer cell tumorigenicity, migration, invasiveness, and lung colonization.
  • SH3BGRL downregulates PFN1 by affecting STUB1 translation or PFN1 degradation, leading to activation of AKT, NF-kB, and WNT pathways.
  • Forced expression of PFN1 neutralizes SH3BGRL-induced metastasis.
  • Clinical data confirm negative correlation between SH3BGRL and PFN1/PTEN, and positive correlation with AKT, NF-kB, and WNT pathway activation.

Conclusions:

  • SH3BGRL is a key driver of breast cancer metastasis and a valuable prognostic factor.
  • SH3BGRL exerts its pro-metastatic effects by downregulating PFN1 and activating oncogenic signaling pathways.
  • SH3BGRL represents a potential therapeutic target for preventing breast cancer progression and metastasis.

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