The HER4 isoform JM-a/CYT2 relates to improved survival in bladder cancer patients but only if the estrogen receptor α is not expressed
Munk, Mathias ; Memon, Ashfaque LU
; Poulsen, Steen S
; Borre, Michael
; Nexo, Ebba
and Sorensen, Boe S
(2013)
In Scandinavian Journal of Clinical and Laboratory Investigation
73(6).
p.13-503
- 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... (More)
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.
(Less)
- author
- Munk, Mathias
; Memon, Ashfaque
LU
; Poulsen, Steen S
; Borre, Michael
; Nexo, Ebba
and Sorensen, Boe S
- publishing date
- 2013-09
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- 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
- in
- Scandinavian Journal of Clinical and Laboratory Investigation
- volume
- 73
- issue
- 6
- pages
- 11 pages
- publisher
- Informa Healthcare
- external identifiers
-
- scopus:84884273269
- pmid:24015958
- ISSN
- 1502-7686
- DOI
- 10.3109/00365513.2013.818706
- language
- English
- LU publication?
- no
- id
- f6fd11a5-5901-4a9e-82d3-018ee2fbc467
- date added to LUP
- 2019-11-22 16:16:01
- date last changed
- 2024-01-02 00:20:55
@article{f6fd11a5-5901-4a9e-82d3-018ee2fbc467,
abstract = {{<p>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.</p>}},
author = {{Munk, Mathias and Memon, Ashfaque and Poulsen, Steen S and Borre, Michael and Nexo, Ebba and Sorensen, Boe S}},
issn = {{1502-7686}},
keywords = {{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}},
language = {{eng}},
number = {{6}},
pages = {{13--503}},
publisher = {{Informa Healthcare}},
series = {{Scandinavian Journal of Clinical and Laboratory Investigation}},
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}},
url = {{http://dx.doi.org/10.3109/00365513.2013.818706}},
doi = {{10.3109/00365513.2013.818706}},
volume = {{73}},
year = {{2013}},
}