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Downregulation of MTAP promotes Tumor Growth and Metastasis by regulating ODC Activity in Breast Cancer

Ying Zhang1, Tian-Tian Zhang1, Lin Gao2

  • 1Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Health Science Center, Shenzhen 518060, Guangdong, China.

International Journal of Biological Sciences
|May 11, 2022
PubMed

Insights

5'-Methylthioadenosine phosphorylase (MTAP) suppresses breast cancer progression. Its downregulation activates ornithine decarboxylase (ODC), promoting metastasis, suggesting MTAP as a therapeutic target.

Area of Science:

  • Oncology
  • Biochemistry
  • Molecular Biology

Background:

  • 5 -Methylthioadenosine phosphorylase (MTAP) is crucial in methionine metabolism and linked to tumor suppression.
  • The MTAP gene's location at 9p21, frequently deleted in breast cancer (BC), highlights its potential role in BC pathogenesis.
  • The precise clinical and biological significance of MTAP in breast cancer remains largely undefined.

Purpose of the Study:

  • To investigate the role of MTAP in breast cancer progression.
  • To elucidate the molecular mechanisms underlying MTAP's function in BC.
  • To evaluate MTAP as a potential therapeutic target for advanced breast cancer.

Main Methods:

  • Quantitative analysis of MTAP expression in primary BC tissues and cell lines.
  • In vitro and in vivo functional assays to assess MTAP's impact on BC cell tumorigenicity.
  • Mechanistic studies involving polyamine levels, ornithine decarboxylase (ODC) activity, and specific inhibitors (DFMO).

Main Results:

  • MTAP was downregulated in 41% of primary BCs and 89% of BC cell lines.
  • Low MTAP expression correlated significantly with poorer patient survival.
  • MTAP suppressed BC cell migration, invasion, angiogenesis, tumor growth, and metastasis.
  • MTAP downregulation increased polyamine levels via ODC activation, which was reversible with ODC inhibition or polyamine supplementation.

Conclusions:

  • MTAP plays a critical metastasis-suppressive role in breast cancer.
  • MTAP regulates metastasis by controlling ODC activity and polyamine levels.
  • MTAP represents a promising therapeutic target for advanced breast cancer treatment.
Keywords:
Breast cancerMTAPMetastasisODCPolyamine biosynthesis

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