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Retinoic acid directs breast cancer cell state changes through regulation of TET2-PKCζ pathway

M-J Wu1,2, M R Kim1,2, Y-S Chen1,2

  • 1Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, USA.

Oncogene
|February 21, 2017
PubMed

Insights

All-trans retinoic acid (ATRA) targets cancer stem cells by activating the RARβ-TET2-miR-200c pathway, suppressing PKCζ. This mechanism reduces stem-like cells in less aggressive cancers and sensitizes resistant cells to tamoxifen.

Area of Science:

  • Cancer Biology
  • Epigenetics
  • Molecular Signaling

Background:

  • The regulation of cancer stem cell (CSC) populations and their differentiation states is critical for understanding cancer progression and treatment resistance.
  • The molecular mechanisms controlling the balance between stem cell-like and differentiated states in cancer remain largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanism by which all-trans retinoic acid (ATRA) influences cancer stem cell populations.
  • To identify novel signaling pathways involved in regulating cancer cell state and CSC pool maintenance.

Main Methods:

  • Investigated the interaction between retinoic acid receptor beta (RARβ) and TET2 in response to ATRA treatment.
  • Analyzed the epigenetic activation of gene targets, including microRNA-200c (miR-200c), by the RARβ-TET2 complex.
  • Assessed the role of miR-200c in targeting protein kinase C zeta (PKCζ) and its impact on cell polarity and stem cell populations.
  • Evaluated the effects of ATRA and PKCζ inhibition on both non-aggressive and aggressive breast cancer cells, including their response to tamoxifen.

Main Results:

  • ATRA induces RARβ-TET2 complex formation, leading to epigenetic activation of miR-200c.
  • TET2-activated miR-200c suppresses PKCζ, a key regulator of stem cell asymmetric division.
  • ATRA treatment decreases stem-like populations in non-tumorigenic and non-aggressive cancer cells by downregulating PKCζ via miR-200c.
  • Aggressive breast cancer cells with TET2-miR-200c dysregulation exhibit ATRA resistance; PKCζ inhibition sensitizes these CSCs to tamoxifen, reducing tumor growth.

Conclusions:

  • A novel RARβ-TET2-miR-200c-PKCζ signaling pathway governs cancer cell state changes and CSC pool dynamics.
  • Targeting PKCζ offers a therapeutic strategy to diminish breast CSCs and overcome tamoxifen resistance in aggressive breast cancers.

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