TY - JOUR

T1 - The HER4 isoform JM-a/CYT2 relates to improved survival in bladder cancer patients but only if the estrogen receptor α is not expressed

AU - Munk, Mathias

AU - Memon, Ashfaque Ahmed

AU - Poulsen, Steen Seier

AU - Borre, Michael Skov

AU - Nexo, Ebba

AU - Sorensen, Boe S

PY - 2013/9

Y1 - 2013/9

N2 - 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.

AB - 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.

U2 - 10.3109/00365513.2013.818706

DO - 10.3109/00365513.2013.818706

M3 - Journal article

C2 - 24015958

VL - 73

SP - 503

EP - 513

JO - Scandinavian Journal of Clinical & Laboratory Investigation

JF - Scandinavian Journal of Clinical & Laboratory Investigation

SN - 0036-5513

IS - 6

ER -