The HER4 isoform JM-a/CYT2 relates to improved survival in bladder cancer patients but only if the estrogen receptor α is not expressed

Research output: Contribution to journalArticle


Bladder cancer tumors expressing human epidermal growth factor receptor 4 (HER4) demonstrate improved patient survival. HER4 isoforms and estrogen receptor alpha (ER-α) can form chaperone complexes causing cell-proliferation. We wanted to explore if HER4 isoforms and ER-α could correlate to poor prognosis in bladder cancers. We developed mRNA assays for HER4 isoforms (JM-a, JM-b, CYT1, and CYT2) and for ER-α. Expression was analyzed in tumors from 85 bladder cancer patients and compared to overall survival (median follow-up of 5.1 years). ER-α was expressed in 38% (n = 32) of tumors but did not correlate to survival (p = 0.4698). HER4 was expressed in 42% (n = 36) and in all cases as the ER-α binding isoform JM-a. The JM-a isoform can be alternatively spliced to either a CYT1 isoform (JM-a/CYT1) or a CYT2 isoform (JM-a/CYT2). All HER4 expressing tumors expressed the JM-a/CYT2 isoform and half of those (18/36) expressed both isoforms. JM-a/CYT2 expression correlated to improved survival (p = 0.004), but not when ER-α was co-expressed (p = 0.897). Immunohistochemistry revealed protein expression of HER4 and ER-α in tumor cells. Growth of RT4 bladder cancer cells, expressing both JM-a/CYT2 and ER-α was inhibited by the specific ER-α inhibitor raloxifene. Likewise, stable transfection with JM-a/CYT2 inhibited the growth of T24 bladder cancer cells, but only when ER-α was inhibited. Our results demonstrate that HER4 JM-a/CYT2 expressing bladder cancers relate to favorable prognosis when ER-α is not co-expressed. In vitro studies indicate that ER-α inhibition may be a useful treatment for patients with tumors expressing both ER-α and HER4 JM-a/CYT2.


  • Mathias Munk
  • Ashfaque Memon
  • Steen S Poulsen
  • Michael Borre
  • Ebba Nexo
  • Boe S Sorensen
External organisations
  • Aarhus University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology


  • Aged, Aged, 80 and over, Amino Acid Sequence, Carcinoma, Papillary/metabolism, Cell Line, Tumor, ErbB Receptors/metabolism, Estrogen Receptor alpha/metabolism, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Molecular Sequence Data, Protein Isoforms/metabolism, Receptor, ErbB-4, Urinary Bladder Neoplasms/metabolism
Original languageEnglish
Pages (from-to)503-13
Number of pages11
JournalScandinavian Journal of Clinical and Laboratory Investigation
Issue number6
Publication statusPublished - 2013 Sep
Publication categoryResearch
Externally publishedYes