Association of ErbB1–4 expression in invasive breast cancer with clinicopathological characteristics and prognosis

Fujiwara, Saori; Ibusuki, Mutsuko; Yamamoto, Shuichi; Yamamoto, Yutaka; Iwase, Hirotaka

doi:10.1007/s12282-012-0415-5

Cited by 23 publications

(26 citation statements)

References 28 publications

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“…In addition, a small fraction of cases had a tumor with distinct HER4 membrane staining. Generally, expression of HER4 is associated to ER-positivity and may predict endocrine responsiveness because of an ERα co-activating role of 4ICD (11,12,23,26). We found a significant association between HER4 N and ER-positivity but no association to prognosis or prediction.…”

Section: Discussionmentioning

confidence: 47%

“…The biological significance of the human epidermal growth factor receptor (HER) 4 is not fully elucidated although it has been associated with ER expression (11,12) and favorable outcome of breast cancer (7,13). Like in other receptor tyrosine kinases, activation results in downstream signaling through pathways such as phosphoinositide 3-kinase (PI3K)/Akt -and Ras/mitogen activated protein kinase (MAPK) (14).…”

Section: Introductionmentioning

confidence: 99%

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

Eremo

Tina

Wegman³

et al. 2015

International Journal of Oncology

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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. IntroductionBreast cancer is the largest group of malignancies among women in the Western world (1) and the majority of breast tumors express estrogen receptors (ER) (2). A common treatment strategy for these patients is blocking estrogen action by tamoxifen (2-4). One of the cellular responses of the ER block is cell cycle arrest in the G1 phase by decreased expression of the cell cycle regulator cyclin D1 (5). Tamoxifen treatment is not efficient for all patients and many experience breast cancer relapse. Endocrine drug resistance may be caused by several mechanisms, such as elevated levels of co-activating proteins involved in ER signaling or changes in tamoxifen metabolism (6-10). Despite extensive research for proteins involved in tamoxifen resistance, no breakthrough of markers has been implicated for clinical practice.The biological significance of the human epidermal growth factor receptor (HER) 4 is not fully elucidated although it has been associated with ER expression (11,12) and favorable outcome of breast cancer (7,13). Like in other receptor tyrosine kinases, activation results in downstream signaling through pathways such as...

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Section: Discussionmentioning

confidence: 47%

Section: Introductionmentioning

confidence: 99%

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

Eremo

Tina

Wegman³

et al. 2015

International Journal of Oncology

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“…The estimated HRs for breast cancer-specific survival (BCSS)/disease-specific survival (DSS)/cancer-specific survival (CSS) were available in 6 publications, which included 1429 samples [16–18, 21, 24, 35]. Further estimated pooled HRs showed that elevated/positive HER4 expression was a favorable marker for BCSS with no heterogeneity (HR = 0.67, CI: 0.47–0.96, P = 0.028, fixed effects; P = 0.066, I 2 = 58.4%; Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

Human epidermal growth factor receptor 4 (HER4) is a favorable prognostic marker of breast cancer: a systematic review and meta-analysis

et al. 2016

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Based on a large cohort of clinical studies involving a total of 8024 patients and reporting the effects of HER4 on breast cancer prognosis, we conducted the first meta-analysis and review of this type. We identified 26 studies published between 1985 and 2016 and assessed the prognostic value of HER4 in breast cancer by either real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR, for mRNA levels) or immunohistochemistry (IHC, for protein levels). Elevated expression of HER4 was significantly associated with longer relapse-free survival (RFS) (HR = 0.63; CI: 0.48−0.83; P = 0.001, random effects). Further subgroup analysis showed that our results were stable irrespective of subtype [Luminal: HR = 0.40, CI: 0.30−0.53, P < 0.001, fixed effects; triple negative breast cancer (TNBC): HR = 0.49, CI: 0.26−0.90, P = 0.02, fixed effects; and HER2-positive: HR = 0.53, CI: 0.40−0.71, P < 0.001, fixed effects]. Cytoplasmic HER4 was more effective than nuclear HER4 (HR = 0.74, CI: 0.60−0.92, P = 0.007, fixed effects) for predicting RFS. HER4 was also found to be a favorable prognostic marker for overall survival (OS) among patients with non-TNBC in the subgroup analysis (Luminal: HR = 0.71, CI: 0.52−0.95, P = 0.023, fixed effects; HER2-positive: HR = 0.48, CI: 0.26−0.89, P = 0.020, fixed effects).

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“…Members of epidermal growth factor-related (Her) receptor tyrosine kinases family, HER1 (ErbB1, EGFR), HER2 (ErbB2, neu), HER3 (ErbB3) and HER4 (ErbB4) showed a critical role in the pathogenesis and tumorigenic processes of BC (4,5). Controversially, the prognostic and predictive value of HER4 expression was indefinite, and both favorable and unfavorable impacts of HER4 expression have been reported (5)(6)(7)(8)(9)(10)(11)(12). Therefore, HER4 can act either as a tumor suppressor or an oncogene in BC.…”

Section: Introductionmentioning

confidence: 99%

HER4 rs1595065 3'UTR Variant is a Possible Risk Factor for HER2 Positivity Among Breast Cancer Patients

Moradi

Tabatabaeian

Sadeghi

et al. 2016

Thrita

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Background: Breast cancer (BC) is the most common neoplasia among females worldwide. Single nucleotide polymorphisms (SNPs) located at the 3 untranslated Region (3 UTR) can alter gene expression pattern through increasing/decreasing microRNAs (miRNAs) binding energy. Human epidermal growth factor receptor 4 (HER4) can act as either a tumor suppressor or an oncogene in breast cancer. Objectives: We proposed that rs1595065 3 UTR variant of HER4 with a different target binding site of miRNAs may have a correlation with risk of BC phenotypes. In the current study, we aimed to evaluate the association between HER4 rs1595065 3'UTR variant and BC pathological features among the Isfahanian population. Moreover, an in-silico prediction was performed to estimate possible function of the rs1595065. Methods: Overall, 156 patients and controls were genotyped using RFLP-PCR. Armitage test for trend was utilized to investigate the association between rs1595065 and susceptibility to BC. The possible change in the interaction between rs1595065 and microRNAs was studied bioinformatically. Results: Bioinformatics analysis using online tools suggest rs1595065 as a polymorphism in the seed region of four miRNAs binding sites including miR-199a-3p, miR-199b-3p, miR-1244 and miR-3129, and C allele can reduce miRNA-mRNA binding occurrence that may increase HER4 expression. Armitage's trend test showed that C allele of rs1595065 was significantly associated with HER2 positivity among patients (C allele vs. T allele, OR = 3.111, P = 0.046). Conclusions: rs1595065 could be recommended as a risk factor in regulating HER4 expression and affecting HER2 positivity incidence among BC patients.

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Association of ErbB1–4 expression in invasive breast cancer with clinicopathological characteristics and prognosis

Cited by 23 publications

References 28 publications

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

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

Human epidermal growth factor receptor 4 (HER4) is a favorable prognostic marker of breast cancer: a systematic review and meta-analysis

HER4 rs1595065 3'UTR Variant is a Possible Risk Factor for HER2 Positivity Among Breast Cancer Patients

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