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Embryonic transcription factor SOX9 drives breast cancer endocrine resistance

Rinath Jeselsohn1,2,3, MacIntosh Cornwell4, Matthew Pun4

  • 1Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215; myles_brown@dfci.harvard.edu rinath_jeselsohn@dfci.harvard.edu.

Proceedings of the National Academy of Sciences of the United States of America
|May 17, 2017
PubMed

Insights

Estrogen receptor (ER) blockade resistance in breast cancer involves a RUNX2-ER complex. This complex up-regulates SOX9, promoting cancer growth and endocrine resistance, necessitating new ER antagonists.

Area of Science:

  • Oncology
  • Endocrinology
  • Molecular Biology

Background:

  • Estrogen receptor (ER) signaling drives most luminal breast cancers and is a key target for endocrine therapy.
  • Tamoxifen is effective but endocrine resistance, particularly in metastatic disease, remains a significant clinical challenge.
  • ER signaling persists and drives tumor progression even after resistance develops.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying tamoxifen resistance in ER-positive breast cancer.
  • To identify novel factors and pathways involved in ER-driven tumor progression despite endocrine therapy.

Main Methods:

  • Analysis of the ER cistrome in tamoxifen-resistant breast cancer cells.
  • Gene expression analysis to identify ER-regulated genes associated with resistance.
  • Validation in clinical samples.

Main Results:

  • A RUNX2-ER complex was identified in tamoxifen-resistant cells.
  • This complex stimulates transcription of genes including SOX9, a stem cell factor.
  • SOX9 up-regulation was sufficient to induce relative endocrine resistance and was validated in clinical samples.

Conclusions:

  • The RUNX2-ER-SOX9 axis is a critical mechanism in tamoxifen resistance.
  • SOX9 plays a pivotal role in promoting proliferation and metastasis in resistant breast cancer.
  • Targeting this pathway may overcome endocrine resistance and necessitates the development of novel ER antagonists.
Keywords:
SOX9breast cancercistromeendocrine resistanceestrogen receptor

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