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HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis

Miao Sun1, Chun-Xiao Song, Hao Huang

  • 1Ben May Department for Cancer Research, Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 30, 2013
PubMed

Insights

High mobility group AT-hook 2 (HMGA2) depletion induces ten-eleven translocation 1 (TET1), which suppresses breast cancer growth. This HMGA2-TET1-HOXA9 pathway is a prognostic signature for patient survival.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Research

Background:

  • The ten-eleven translocation (TET) family of enzymes initiates DNA demethylation and is implicated in various cancers.
  • The precise mechanisms underlying TET enzyme function in tumorigenesis remain largely unelucidated.

Purpose of the Study:

  • To identify upstream activators and downstream effectors of TET1 in the context of breast cancer.
  • To elucidate the role of the HMGA2-TET1-HOXA9 signaling pathway in breast cancer progression and prognosis.

Main Methods:

  • Utilized human breast cancer cell lines and a genetically engineered mouse model.
  • Investigated the effects of high mobility group AT-hook 2 (HMGA2) depletion on TET1 expression.
  • Analyzed TET1 binding and demethylation activity at its own promoter and HOXA gene promoters.
  • Assessed the impact of TET1 and HOXA9 on tumor growth and metastasis in mouse xenografts.

Main Results:

  • Depletion of HMGA2 was found to induce TET1 expression.
  • TET1 directly demethylates its own promoter and the promoters of HOXA genes, thereby enhancing its expression and that of HOXA genes (e.g., HOXA7, HOXA9).
  • Both TET1 and HOXA9 demonstrated suppressive effects on breast tumor growth and metastasis in vivo.
  • The HMGA2-TET1-HOXA9 gene pathway is coordinately regulated and serves as a prognostic signature for patient survival.

Conclusions:

  • The HMGA2-TET1-HOX signaling pathway plays a critical role in the epigenetic regulation of human breast cancer.
  • Targeting DNA methylation within specific subpopulations presents a potential therapeutic strategy for breast cancer.

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