MUC16 induced rapid G2/M transition via interactions with JAK2 for increased proliferation and anti-apoptosis in breast cancer cells

Oncogene. 2012 Feb 16;31(7):805-17. doi: 10.1038/onc.2011.297. Epub 2011 Jul 25.


MUC16/CA125 is a tumor marker currently used in clinics for the follow-up of patients with ovarian cancer. However, MUC16 expression is not entirely restricted to ovarian malignancies and has been reported in other cancers including breast cancer. Although it is well established as a biomarker, function of MUC16 in cancer remains to be elucidated. In the present study, we investigated the role of MUC16 in breast cancer and its underlying mechanisms. Interestingly, our results showed that MUC16 is overexpressed in breast cancer tissues whereas not expressed in non-neoplastic ducts. Further, stable knockdown of MUC16 in breast cancer cells (MDA MB 231 and HBL100) resulted in significant decrease in the rate of cell growth, tumorigenicity and increased apoptosis. In search of a mechanism for breast cancer cell proliferation we found that MUC16 interacts with the ezrin/radixin/moesin domain-containing protein of Janus kinase (JAK2) as demonstrated by the reciprocal immunoprecipitation method. These interactions mediate phosphorylation of STAT3 (Tyr705), which might be a potential mechanism for MUC16-induced proliferation of breast cancer cells by a subsequent co-transactivation of transcription factor c-Jun. Furthermore, silencing of MUC16 induced G2/M arrest in breast cancer cells through downregulation of Cyclin B1 and decreased phosphorylation of Aurora kinase A. This in turn led to enhanced apoptosis in the MUC16-knockdown breast cancer cells through Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated extrinsic apoptotic pathway with the help of c-Jun N-terminal kinase signaling. Collectively, our results suggest that MUC16 has a dual role in breast cancer cell proliferation by interacting with JAK2 and by inhibiting the apoptotic process through downregulation of TRAIL.

Publication types

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

MeSH terms

  • Apoptosis*
  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • CA-125 Antigen / genetics
  • CA-125 Antigen / metabolism*
  • Cell Division
  • Cell Line, Tumor
  • Cell Proliferation*
  • Cyclin B1 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Female
  • G2 Phase
  • Humans
  • Immunohistochemistry
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Models, Biological
  • Phosphorylation
  • Protein Binding
  • RNA Interference
  • STAT3 Transcription Factor / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / metabolism


  • CA-125 Antigen
  • Cyclin B1
  • Cyclin-Dependent Kinase Inhibitor p21
  • MUC16 protein, human
  • Membrane Proteins
  • STAT3 Transcription Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • JAK2 protein, human
  • Janus Kinase 2
  • JNK Mitogen-Activated Protein Kinases