title: The HER4 isoform JM-a/CYT2 relates to improved survival in bladder cancer patients but only if the estrogen receptor α is not expressed.
abstract: 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.
authors.affiliation: Department of Clinical Biochemistry, Aarhus University Hospital (NBG).
authors.forename: Mathias
authors.initials: M
authors.lastname: Munk
authors.forename: Ashfaque
authors.initials: A
authors.lastname: Memon
authors.forename: Steen S
authors.initials: SS
authors.lastname: Poulsen
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.forename: Ebba
authors.initials: E
authors.lastname: Nexo
authors.forename: Boe S
authors.initials: BS
authors.lastname: Sorensen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D002291:Carcinoma, Papillary / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000378:metabolism; D066247:Receptor, ErbB-4; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000401:mortality
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D020033:Protein Isoforms; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4