Par-4 downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy

Cancer Cell. 2013 Jul 8;24(1):30-44. doi: 10.1016/j.ccr.2013.05.007. Epub 2013 Jun 13.


Most deaths from breast cancer result from tumor recurrence, but mechanisms underlying tumor relapse are largely unknown. We now report that Par-4 is downregulated during tumor recurrence and that Par-4 downregulation is necessary and sufficient to promote recurrence. Tumor cells with low Par-4 expression survive therapy by evading a program of Par-4-dependent multinucleation and apoptosis that is otherwise engaged following treatment. Low Par-4 expression is associated with poor response to neoadjuvant chemotherapy and an increased risk of relapse in patients with breast cancer, and Par-4 is downregulated in residual tumor cells that survive neoadjuvant chemotherapy. Our findings identify Par-4-induced multinucleation as a mechanism of cell death in oncogene-addicted cells and establish Par-4 as a negative regulator of breast cancer recurrence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / physiology*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / etiology*
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology
  • Cardiac Myosins / metabolism
  • Death-Associated Protein Kinases
  • Down-Regulation
  • Female
  • Humans
  • Mice
  • Myosin Light Chains / metabolism
  • Neoplasm Recurrence, Local / etiology*
  • Phosphorylation
  • Receptor, ErbB-2 / analysis
  • Tumor Suppressor Protein p53 / physiology


  • Apoptosis Regulatory Proteins
  • Myosin Light Chains
  • Tumor Suppressor Protein p53
  • myosin light chain 2
  • prostate apoptosis response-4 protein
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Death-Associated Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cardiac Myosins