HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen

Göthlin Eremo,Anna; Tina,Elisabet; Wegman,Pia; Stål,Olle; Fransén,Karin; Fornander,Tommy; Wingren,Sten

doi:10.3892/ijo.2015.3108

HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen

Authors:
- Anna Göthlin Eremo
- Elisabet Tina
- Pia Wegman
- Olle Stål
- Karin Fransén
- Tommy Fornander
- Sten Wingren
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Affiliations: Faculty of Medicine and Health, School of Health and Medical Sciences, Örebro University, SE-701 82 Örebro, Sweden, Clinical Research Centre, Örebro University Hospital, SE-701 85 Örebro, Sweden, Department of Clinical Genetics, University Hospital, SE-581 85 Linköping, Sweden, Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, SE-581 85 Linköping, Sweden, Department of Oncology, Karolinska University Hospital, Karolinska Institute, SE-171 76 Stockholm, Sweden
Published online on: July 28, 2015 https://doi.org/10.3892/ijo.2015.3108
Pages: 1311-1320

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Abstract

The human epidermal growth factor receptor (HER) 4 is a relative of HER2 and has been associated to endocrine breast cancer and prediction of tamoxifen response. In addition to PI3K/Akt and MAPK pathway activation, ligand binding to HER4 triggers proteolytic cleavage and release of an intracellular receptor domain (4ICD) with signaling properties. The aim of the present study was to analyze HER4 protein expression and intracellular localization in breast cancer tissue from patients randomized to treatment with or without adjuvant tamoxifen. To investigate HER4 expression and localization in response to estradiol (E2) and 4-hydroxytamoxifen (4-OHT) exposure, we also performed in vitro studies. Cytoplasmic, nuclear and membrane expression of HER4 protein was evaluated by immunohistochemical staining in tumor tissue from 912 breast cancer patients. Three different breast epithelia cancer cell lines were exposed to E2 and 4-OHT and mRNA expression was analyzed using qPCR. Further, nuclear and cytoplasmic proteins were separated and analyzed with western blotting. We found an association between nuclear HER4 protein expression and ER-positivity (P=0.004). Furthermore, significant association was found between cytoplasmic HER4 and ER-negativity (P<0.0005), PgR-negativity (P<0.0005), tumor size >20 mm (P=0.001) and HER2-negativity (P=0.008). However, no overall significance of HER4 on recurrence-free survival was found. After E2 exposure, HER4 mRNA and protein expression had decreased in two cell lines in vitro yet no changes in nuclear or cytoplasmic protein fractions were seen. In conclusion, nuclear HER4 seem to be co-located with ER, however, we did not find support for overall HER4 expression in independently predicting response of tamoxifen treatment. The possible influence of separate isoforms was not tested and future studies may further evaluate HER4 significance.

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1	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar
2	Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, Giordano SH, Hudis CA, Rowden D, Solky AJ, et al: Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J Clin Oncol. 32:2255–2269. 2014. View Article : Google Scholar : PubMed/NCBI
3	Lumachi F, Brunello A, Maruzzo M, Basso U and Basso SM: Treatment of estrogen receptor-positive Breast Cancer. Curr Med Chem. 20:596–604. 2013. View Article : Google Scholar : PubMed/NCBI
4	Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, McGale P, Pan HC, Taylor C, Wang YC, et al; Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: Patient-level meta-analysis of randomised trials. Lancet. 378:771–784. 2011. View Article : Google Scholar : PubMed/NCBI
5	Kilker RL, Hartl MW, Rutherford TM and Planas-Silva MD: Cyclin D1 expression is dependent on estrogen receptor function in tamoxifen-resistant breast cancer cells. J Steroid Biochem Mol Biol. 92:63–71. 2004. View Article : Google Scholar : PubMed/NCBI
6	Wegman P, Elingarami S, Carstensen J, Stål O, Nordenskjöld B and Wingren S: Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res. 9:R72007. View Article : Google Scholar : PubMed/NCBI
7	Ghayad SE, Vendrell JA, Ben Larbi S, Dumontet C, Bieche I and Cohen PA: Endocrine resistance associated with activated ErbB system in breast cancer cells is reversed by inhibiting MAPK or PI3K/Akt signaling pathways. Int J Cancer. 126:545–562. 2010. View Article : Google Scholar
8	Lindberg K, Helguero LA, Omoto Y, Gustafsson JA and Haldosén LA: Estrogen receptor β represses Akt signaling in breast cancer cells via downregulation of HER2/HER3 and upregulation of PTEN: Implications for tamoxifen sensitivity. Breast Cancer Res. 13:R432011. View Article : Google Scholar
9	Normanno N, Di Maio M, De Maio E, De Luca A, de Matteis A, Giordano A and Perrone F; NCI-Naple Breast Cancer Group. Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer. Endocr Relat Cancer. 12:721–747. 2005. View Article : Google Scholar : PubMed/NCBI
10	Ring A and Dowsett M: Mechanisms of tamoxifen resistance. Endocr Relat Cancer. 11:643–658. 2004. View Article : Google Scholar : PubMed/NCBI
11	Knowlden JM, Gee JM, Seery LT, Farrow L, Gullick WJ, Ellis IO, Blamey RW, Robertson JF and Nicholson RI: c-erbB3 and c-erbB4 expression is a feature of the endocrine responsive phenotype in clinical breast cancer. Oncogene. 17:1949–1957. 1998. View Article : Google Scholar : PubMed/NCBI
12	Fujiwara S, Ibusuki M, Yamamoto S, Yamamoto Y and Iwase H: Association of ErbB1-4 expression in invasive breast cancer with clinicopathological characteristics and prognosis. Breast Cancer. 21:472–481. 2012. View Article : Google Scholar : PubMed/NCBI
13	Guler G, Iliopoulos D, Guler N, Himmetoglu C, Hayran M and Huebner K: Wwox and Ap2gamma expression levels predict tamoxifen response. Clin Cancer Res. 13:6115–6121. 2007. View Article : Google Scholar : PubMed/NCBI
14	Kainulainen V, Sundvall M, Määttä JA, Santiestevan E, Klagsbrun M and Elenius K: A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis. J Biol Chem. 275:8641–8649. 2000. View Article : Google Scholar : PubMed/NCBI
15	Elenius K, Corfas G, Paul S, Choi CJ, Rio C, Plowman GD and Klagsbrun M: A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester. J Biol Chem. 272:26761–26768. 1997. View Article : Google Scholar : PubMed/NCBI
16	Elenius K, Choi CJ, Paul S, Santiestevan E, Nishi E and Klagsbrun M: Characterization of a naturally occurring ErbB4 isoform that does not bind or activate phosphatidyl inositol 3-kinase. Oncogene. 18:2607–2615. 1999. View Article : Google Scholar : PubMed/NCBI
17	Muraoka-Cook RS, Sandahl MA, Strunk KE, Miraglia LC, Husted C, Hunter DM, Elenius K, Chodosh LA and Earp HS III: ErbB4 splice variants Cyt1 and Cyt2 differ by 16 amino acids and exert opposing effects on the mammary epithelium in vivo. Mol Cell Biol. 29:4935–4948. 2009. View Article : Google Scholar : PubMed/NCBI
18	Sundvall M, Veikkolainen V, Kurppa K, Salah Z, Tvorogov D, van Zoelen EJ, Aqeilan R and Elenius K: Cell death or survival promoted by alternative isoforms of ErbB4. Mol Biol Cell. 21:4275–4286. 2010. View Article : Google Scholar : PubMed/NCBI
19	Sundvall M, Peri L, Määttä JA, Tvorogov D, Paatero I, Savisalo M, Silvennoinen O, Yarden Y and Elenius K: Differential nuclear localization and kinase activity of alternative ErbB4 intracellular domains. Oncogene. 26:6905–6914. 2007. View Article : Google Scholar : PubMed/NCBI
20	Naresh A, Thor AD, Edgerton SM, Torkko KC, Kumar R and Jones FE: The HER4/4ICD estrogen receptor coactivator and BH3-only protein is an effector of tamoxifen-induced apoptosis. Cancer Res. 68:6387–6395. 2008. View Article : Google Scholar : PubMed/NCBI
21	Naresh A, Long W, Vidal GA, Wimley WC, Marrero L, Sartor CI, Tovey S, Cooke TG, Bartlett JM and Jones FE: The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells. Cancer Res. 66:6412–6420. 2006. View Article : Google Scholar : PubMed/NCBI
22	Thor AD, Edgerton SM and Jones FE: Subcellular localization of the HER4 intracellular domain, 4ICD, identifies distinct prognostic outcomes for breast cancer patients. Am J Pathol. 175:1802–1809. 2009. View Article : Google Scholar : PubMed/NCBI
23	Rokicki J, Das PM, Giltnane JM, Wansbury O, Rimm DL, Howard BA and Jones FE: The ERalpha coactivator, HER4/4ICD, regulates progesterone receptor expression in normal and malignant breast epithelium. Mol Cancer. 9:1502010. View Article : Google Scholar : PubMed/NCBI
24	Rutqvist LE and Johansson H: Long-term follow-up of the randomized Stockholm trial on adjuvant tamoxifen among post-menopausal patients with early stage breast cancer. Acta Oncol. 46:133–145. 2007. View Article : Google Scholar
25	Subik K, Lee JF, Baxter L, Strzepek T, Costello D, Crowley P, Xing L, Hung MC, Bonfiglio T, Hicks DG, et al: The expression patterns of ER, PR, HER2, CK5/6, EGFR, Ki-67 and AR by immunohistochemical analysis in breast cancer cell lines. Breast Cancer (Auckl). 4:35–41. 2010.
26	Han W and Jones FE: HER4 selectively coregulates estrogen stimulated genes associated with breast tumor cell proliferation. Biochem Biophys Res Commun. 443:458–463. 2014. View Article : Google Scholar :
27	Fujiwara S, Hung M, Yamamoto-Ibusuk CM, Yamamoto Y, Yamamoto S, Tomiguchi M, Takeshita T, Hayashi M, Sueta A and Iwase H: The localization of HER4 intracellular domain and expression of its alternately-spliced isoforms have prognostic significance in ER⁺ HER2⁻ breast cancer. Oncotarget. 5:3919–3930. 2014. View Article : Google Scholar : PubMed/NCBI
28	Barnes NL, Khavari S, Boland GP, Cramer A, Knox WF and Bundred NJ: Absence of HER4 expression predicts recurrence of ductal carcinoma in situ of the breast. Clin Cancer Res. 11:2163–2168. 2005. View Article : Google Scholar : PubMed/NCBI
29	Hutcheson IR, Goddard L, Barrow D, McClelland RA, Francies HE, Knowlden JM, Nicholson RI and Gee JM: Fulvestrant-induced expression of ErbB3 and ErbB4 receptors sensitizes oestrogen receptor-positive breast cancer cells to heregulin β1. Breast Cancer Res. 13:R292011. View Article : Google Scholar
30	Revillion F, Pawlowski V, Lhotellier V, Louchez MM and Peyrat JP: mRNA expression of the type I growth factor receptors in the human breast cancer cells MCF-7: Regulation by estradiol and tamoxifen. Anticancer Res. 23B:1455–1460. 2003.