Tumor Biol. DOI 10.1007/s13277-014-1975-0
RESEARCH ARTICLE
The expression of β-catenin in different subtypes of breast cancer and its clinical significance Shuguang Li & Shanshan Li & Ying Sun & Li Li
Received: 2 February 2014 / Accepted: 15 April 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract The Wnt/β-catenin signaling pathway is implicated in mammary oncogenesis. Reports of β-catenin expression and its association with outcome in breast cancer are controversial. This study was performed to address the distribution of β-catenin expression in invasive breast cancer and the correlation between β-catenin expression and survival of breast cancer patients, and to determine whether β-catenin was specifically activated in any molecular subtypes. Immunohistochemistry was performed on a tissue microarray containing 169 invasive breast cancers to detect expression of β-catenin. One hundred thirty one of the 169 patients were followed up. Correlation between β-catenin expression and different molecular subtypes was determined using chi-square analysis. Overall survival (OS) was analyzed by KaplanMeier method with log-rank test. The invasive breast cancer displayed the different patterns of β-catenin expression from normal tissues with significantly increased cytoplasmic and nuclear staining of β-catenin. Aberrant β-catenin expression was observed in 109 in the 169 cases (64.50 %), and there was no difference in β-catenin expression in the four molecular subtypes. Furthermore, aberrant β-catenin expression was significantly associated with adverse outcome not only in the entire cohort but also in each of the different molecular subtypes. β-catenin activation is preferentially found and is associated with a poor clinical outcome in invasive breast cancer independent of molecular subtype.
S. Li : Y. Sun : L. Li (*) Department of Medical Oncology, Cancer Center, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, 250012 Jinan, China e-mail: [email protected] S. Li Department of Oncology, Dongguan Houjie Hospital affiliated to Guangdong Medical College, Dongguan, Guangdong, China
Keywords Breast cancer . β-catenin . Molecular subtype . Prognosis
Introduction Breast cancer is one of the most frequently diagnosed cancers in females worldwide and one of the most investigated diseases which management has moved very rapidly into the molecular era. The current therapies merge clinical, pathological, and molecular understanding to improve outcomes, and the mortality has been falling steadily. One of the major challenges in breast cancer treatment stems from the fact that it is a heterogeneous disease comprised at least four main subtypes [1, 2]. Three distinct biomarkers including estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor-2 (HER2) are used to define four main molecular classes of breast cancer: luminal-A cancer, luminal-B cancer, HER2-positive cancer, and triple-negative cancer. Although these major subtypes of breast cancer have been considered as practical variables used to predict cancer patient survival and determine the appropriate therapy, different patterns of gene expression analysis stratified by these subtypes used in prognostic evaluation remain a clinical challenge [3, 4]. There is a pressing need to develop new biomarkers and therapeutic strategies to combat the disease. The Wnt/β-catenin signaling pathway is known to be important in many biological processes, such as embryonic development, stem cell growth, and tumor cell survival [5–8]. In this signaling pathway, β-catenin is a multifunctional protein that plays a critical role in cell-cell adhesion by linking cadherins to the actin cytoskeleton and is an important transcriptional activator of canonical Wnt-mediated gene expression [9, 10]. Activation of the Wnt signaling pathway by Wnt ligands binding to two receptor molecules, frizzled proteins,
Tumor Biol.
and lipoprotein receptor-related proteins 5 and 6 (LRP-5/6) prevents phosphorylation and degradation of β-catenin by the GSK3β/APC/axin destruction complex. After that, β-catenin accumulates in the cytoplasm and is translocated to the nucleus where it interacts with transcriptional activators to modulate a number of downstream target genes associated with increased growth, invasion, and cellular transformation, such as cyclin D1 and c-MYC [11–13]. Wnt/β-catenin signaling has been implicated in different stages of mammary gland development and is important for mammary oncogenesis [14–16]. Reports of β-catenin expression in breast cancer and its association with outcome are limited and controversial. Some authors have reported that aberrant β-catenin expression is associated with poor prognosis [17–19], but others have failed to demonstrate a correlation between β-catenin aberrant expression and outcome [20–22]. The objective of the current study was to assess the distribution of β-catenin expression in invasive breast cancer and the correlation between β-catenin expression and survival of breast cancer patients, and to determine whether β-catenin was specifically activated in any molecular subtypes.
Immunohistochemistry Immunohistochemistry was performed on tissue microarray sections. The tissue microarray sections were deparaffinized and rehydrated with a series of grades of alcohol. Endogenous peroxidases were blocked with 0.3 % hydrogen peroxide. Then, sections were incubated with either anti-β-catenin antibody (1:100; Zymed, San Francisco, CA, USA) or anti-Ki67 antibody (1:100; Zymed) at 4 °C overnight, or with either antiER antibody (1:200; Zymed), anti-PR antibody (1:200; Zymed), or anti-HER2 antibody (1:100; Zymed) at 37 °C for 2 h. After incubation with secondary antibody for 20 min at 37 °C, color was developed by incubation with 3,3′-diaminobenzidine tetra-hydrochloride (DAB). The sections were counterstained with hematoxylin. All steps were preceded by rinsing with phosphate-buffered saline (PBS; pH 7.6). Negative control sections were processed excluding the primary antibody but including all other steps of the procedure. Immunohistochemical staining results were assessed independently by two breast pathologists who were unaware of the clinical and pathologic information. Five areas of every section were chosen randomly, and 200 carcinoma cells per area were counted. Protein expression was assessed according to the immunoreactivity score (IRS) [26]. The score of every section is the average value of the five areas.
Materials and methods Statistical analysis Study patients and tissues In this study, 169 formalin-fixed, paraffin-embedded tissues of invasive breast cancer from May 2007 to June 2008 were obtained from the surgical pathology archive of the Qilu Hospital of Shandong University. There were survival data on 131 of the 169 patients with a median follow-up of 48 months. The histological grading of invasive breast cancer was performed using the modified Bloom-Richardson scoring system [23] and a three-tier grading system World Health Organization-based system modified by Fang and Thomas [24], respectively. Breast cancer subtypes were previously analyzed for the expression of immunohistochemical markers and defined as luminal-A cancer, luminal-B cancer, HER2positive cancer, and triple-negative cancer according to Perou et al [1].
Tissue microarray construction A total of eight tissue microarrays containing two cores of each sample were constructed from formalin-fixed, paraffinembedded invasive carcinomas and adjacent histological normal epithelium. The tissue microarrays were produced with the use of the MTA-1 manual tissue arrayer (Beecher Instruments, Woodland, CA, USA) as described [25].
The follow-up period was defined as the time from surgery to the last observation for censored or death for complete observations. Overall survival was defined as the time between the date of the primary surgery and the date of death or December 2012. Correlation between β-catenin expression and different molecular subtypes was determined using chi-square analysis. Survival curves were plotted by using the Kaplan-Meier method, and the differences between survival curves were compared by means of the log-rank test. Statistics were analyzed using SPSS 18.0 (Chicago, IL, USA). P0.05
Normal expression n (%)
Aberrant expression n (%)
Total
19 (44.19) 23 (35.94) 10 (41.67) 8 (21.05) 60 (35.50)
24 (55.81) 41 (64.06) 14 (58.33) 30 (78.95) 109 (64.50)
43 64 24 38 169
Kaplan-Meier overall survival curves were generated to assess prognostic ability of β-catenin. Of the 169 patients with invasive breast cancer in our cohort, we had data on overall survival on 131 of them with a median follow-up of 48 months. Those patients with aberrant β-catenin expression had a significantly reduced overall survival in the entire cohort and in each of the different molecular subtypes (Fig. 2a–e).
Discussion The role of Wnt/β-catenin signaling in human tumors has been supported by many studies, but to our knowledge, the exact role in breast cancer remains unclear. The possible explanations are these studies did not categorize the βcatenin subcellular localization and molecular subtypes. We therefore evaluated β-catenin expression in a cohort of invasive breast cancers with known patient phenotypes and outcome. Immunohistochemical studies of β-catenin in breast cancer have shown mixed results in terms of subcellular localization. Earlier reports focused on the loss or reduction of membranous expression of β-catenin [20, 29–32], but recent studies have demonstrated positive cytoplasmic/nuclear expression of β-catenin in breast cancer which is considered to be indicative of Wnt pathway activation [19, 27, 28, 33, 34]. In our study, β-catenin expression is located mainly in the membrane in normal cells, which is consistent with the previous results [31, 32], and β-catenin cytoplasmic expression in invasive breast
Tumor Biol.
Fig. 2 Aberrant β-catenin expression is associated with poor survival independent of molecular subtype. Kaplan-Meier overall survival curves are presented according to expression of β-catenin for the entire cohort (a),
luminal-A (b), luminal-B (c), HER2-positive (d), and triple-negative (e), respectively
Tumor Biol.
cancer is higher than that in normal tissue. Further studies with more sophisticated and in situ assessments of β-catenin protein levels may be warranted. Numerous prognostic factors have been evaluated in breast cancer patients to predict clinical outcome; furthermore, they are thought to be important in finding molecular mechanisms of abnormal tumor proliferation and potential targets for therapeutic intervention. There are multiple lines of evidence that suggest an important role for β-catenin in breast cancer. A recent study, which showed patients who had high coexpression of β-catenin and p53 had a significantly worse outcome, has demonstrated that a combined analysis of multiple markers, notably β-catenin and p53, may enhance the prognostic capabilities compared with individual markers [35]. In our study, β-catenin expression in a large series of invasive breast cancinomas is aberrant, which expands on the possibility that activation of signaling via the Wnt pathway is an important component of invasive breast cancinomas [14–16]. In an attempt to determine whether it was specifically activated in any molecular subtypes, we compared the expression of β-catenin in the four molecular subtypes. While some studies have demonstrated that the expression of β-catenin is significantly different in the four molecular subtypes and is enriched in triple-negative subtype [21, 28, 32, 34], we are unable to detect the difference of β-catenin expression in the four molecular subtypes. Furthermore, our results have shown that aberrant β-catenin expression is significantly associated with adverse outcome not only in the entire cohort but also in each of the different molecular subtypes, which suggests βcatenin may identify a subset of patients within each molecular subtype who have an even worse outcome. β-catenin together with molecular subtype might be helpful in identifying patients who might benefit from early systemic treatment. Several studies have showed Wnt/β-catenin activation is an important feature of triple-negative breast cancers and is predictive of worse overall survival [21, 28, 32, 34], while the recent evidences indicate that Wnt/β-catenin activation leads to HER2mediated breast cancer progression [36, 37] and is a potential mechanism involved in trastuzumab resistance in HER2overexpressing breast cancers [38]. As for luminal subtype, there is also data supporting Wnt/β-catenin signaling is involved in acquired tamoxifen resistance [39, 40]. The role of the Wnt/βcatenin pathway is still inconclusive in invasive breast cancer. This is not surprising because of the complexity of this molecular pathway and crosstalk between other signaling pathways. In conclusion, β-catenin is a valuable biomarker in predicting the prognosis, and its aberrant expression indicates poor outcome of invasive breast cancer. The precise mechanism between adverse outcome and Wnt/β-catenin pathway activation is still unknown. Through further understanding of the role of Wnt/β-catenin signaling activation, it is possible that β-catenin would be a potential therapeutic target for breast cancer.
Acknowledgments This study was supported by grants from the Shandong Province Science and Technology Development Projects (2013GSF11839) and Independent Innovation Foundation for Universities and Colleges in Jinan City (201311023). Conflicts of interest None.
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Tumor Biol. 19. Lopez-Knowles E, Zardawi SJ, McNeil CM, Millar EK, Crea P, Musgrove EA, et al. Cytoplasmic localization of beta-catenin is a marker of poor outcome in breast cancer patients. Cancer Epidemiol Biomarkers Prev. 2010;19:301–9. 20. Bukholm IK, Nesland JM, Karesen R, Jacobsen U, Borresen-Dale AL. E-cadherin and alpha-, beta-, and gamma-catenin protein expression in relation to metastasis in human breast carcinoma. J Pathol. 1998;185:262–6. 21. Pedersen KB, Nesland JM, Fodstad O, Maelandsmo GM. Expression of S100A4, E-cadherin, alpha- and beta-catenin in breast cancer biopsies. Br J Cancer. 2002;87:1281–6. 22. Wong SC, Lo SF, Lee KC, Yam JW, Chan JK, Wendy Hsiao WL. Expression of frizzled-related protein and Wnt-signalling molecules in invasive human breast tumours. J Pathol. 2002;196:145–53. 23. Elston EW, Ellis IO. Method for grading breast cancer. J Clin Pathol. 1993;46:189–90. 24. Fang F, Damjanov I. Tumors of the breast. Cancer Grading Manual. 2007. p. 75–81. 25. Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998;4:844–7. 26. Remmele W, Schicketanz KH. Immunohistochemical determination of estrogen and progesterone receptor content in human breast cancer. Computer-assisted image analysis (QIC score) vs. subjective grading (IRS). Pathol Res Pract. 1993;189:862–6. 27. Hayes MJ, Thomas D, Emmons A, Giordano TJ, Kleer CG. Genetic changes of Wnt pathway genes are common events in metaplastic carcinomas of the breast. Clin Cancer Res. 2008;14:4038–44. 28. Khramtsov AI, Khramtsova GF, Tretiakova M, Huo D, Olopade OI, Goss KH. Wnt/beta-catenin pathway activation is enriched in basallike breast cancers and predicts poor outcome. Am J Pathol. 2010;176:2911–20. 29. Bankfalvi A, Terpe HJ, Breukelmann D, Bier B, Rempe D, Pschadka G, et al. Immunophenotypic and prognostic analysis of E-cadherin and beta-catenin expression during breast carcinogenesis and tumour progression: a comparative study with CD44. Histopathology. 1999;34:25–34. 30. Gonzalez MA, Pinder SE, Wencyk PM, Bell JA, Elston CW, Nicholson RI, et al. An immunohistochemical examination of the expression of E-cadherin, alpha- and beta/gamma-catenins, and
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RESEARCH ARTICLE
The expression of β-catenin in different subtypes of breast cancer and its clinical significance Shuguang Li & Shanshan Li & Ying Sun & Li Li
Received: 2 February 2014 / Accepted: 15 April 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract The Wnt/β-catenin signaling pathway is implicated in mammary oncogenesis. Reports of β-catenin expression and its association with outcome in breast cancer are controversial. This study was performed to address the distribution of β-catenin expression in invasive breast cancer and the correlation between β-catenin expression and survival of breast cancer patients, and to determine whether β-catenin was specifically activated in any molecular subtypes. Immunohistochemistry was performed on a tissue microarray containing 169 invasive breast cancers to detect expression of β-catenin. One hundred thirty one of the 169 patients were followed up. Correlation between β-catenin expression and different molecular subtypes was determined using chi-square analysis. Overall survival (OS) was analyzed by KaplanMeier method with log-rank test. The invasive breast cancer displayed the different patterns of β-catenin expression from normal tissues with significantly increased cytoplasmic and nuclear staining of β-catenin. Aberrant β-catenin expression was observed in 109 in the 169 cases (64.50 %), and there was no difference in β-catenin expression in the four molecular subtypes. Furthermore, aberrant β-catenin expression was significantly associated with adverse outcome not only in the entire cohort but also in each of the different molecular subtypes. β-catenin activation is preferentially found and is associated with a poor clinical outcome in invasive breast cancer independent of molecular subtype.
S. Li : Y. Sun : L. Li (*) Department of Medical Oncology, Cancer Center, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, 250012 Jinan, China e-mail: [email protected] S. Li Department of Oncology, Dongguan Houjie Hospital affiliated to Guangdong Medical College, Dongguan, Guangdong, China
Keywords Breast cancer . β-catenin . Molecular subtype . Prognosis
Introduction Breast cancer is one of the most frequently diagnosed cancers in females worldwide and one of the most investigated diseases which management has moved very rapidly into the molecular era. The current therapies merge clinical, pathological, and molecular understanding to improve outcomes, and the mortality has been falling steadily. One of the major challenges in breast cancer treatment stems from the fact that it is a heterogeneous disease comprised at least four main subtypes [1, 2]. Three distinct biomarkers including estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor-2 (HER2) are used to define four main molecular classes of breast cancer: luminal-A cancer, luminal-B cancer, HER2-positive cancer, and triple-negative cancer. Although these major subtypes of breast cancer have been considered as practical variables used to predict cancer patient survival and determine the appropriate therapy, different patterns of gene expression analysis stratified by these subtypes used in prognostic evaluation remain a clinical challenge [3, 4]. There is a pressing need to develop new biomarkers and therapeutic strategies to combat the disease. The Wnt/β-catenin signaling pathway is known to be important in many biological processes, such as embryonic development, stem cell growth, and tumor cell survival [5–8]. In this signaling pathway, β-catenin is a multifunctional protein that plays a critical role in cell-cell adhesion by linking cadherins to the actin cytoskeleton and is an important transcriptional activator of canonical Wnt-mediated gene expression [9, 10]. Activation of the Wnt signaling pathway by Wnt ligands binding to two receptor molecules, frizzled proteins,
Tumor Biol.
and lipoprotein receptor-related proteins 5 and 6 (LRP-5/6) prevents phosphorylation and degradation of β-catenin by the GSK3β/APC/axin destruction complex. After that, β-catenin accumulates in the cytoplasm and is translocated to the nucleus where it interacts with transcriptional activators to modulate a number of downstream target genes associated with increased growth, invasion, and cellular transformation, such as cyclin D1 and c-MYC [11–13]. Wnt/β-catenin signaling has been implicated in different stages of mammary gland development and is important for mammary oncogenesis [14–16]. Reports of β-catenin expression in breast cancer and its association with outcome are limited and controversial. Some authors have reported that aberrant β-catenin expression is associated with poor prognosis [17–19], but others have failed to demonstrate a correlation between β-catenin aberrant expression and outcome [20–22]. The objective of the current study was to assess the distribution of β-catenin expression in invasive breast cancer and the correlation between β-catenin expression and survival of breast cancer patients, and to determine whether β-catenin was specifically activated in any molecular subtypes.
Immunohistochemistry Immunohistochemistry was performed on tissue microarray sections. The tissue microarray sections were deparaffinized and rehydrated with a series of grades of alcohol. Endogenous peroxidases were blocked with 0.3 % hydrogen peroxide. Then, sections were incubated with either anti-β-catenin antibody (1:100; Zymed, San Francisco, CA, USA) or anti-Ki67 antibody (1:100; Zymed) at 4 °C overnight, or with either antiER antibody (1:200; Zymed), anti-PR antibody (1:200; Zymed), or anti-HER2 antibody (1:100; Zymed) at 37 °C for 2 h. After incubation with secondary antibody for 20 min at 37 °C, color was developed by incubation with 3,3′-diaminobenzidine tetra-hydrochloride (DAB). The sections were counterstained with hematoxylin. All steps were preceded by rinsing with phosphate-buffered saline (PBS; pH 7.6). Negative control sections were processed excluding the primary antibody but including all other steps of the procedure. Immunohistochemical staining results were assessed independently by two breast pathologists who were unaware of the clinical and pathologic information. Five areas of every section were chosen randomly, and 200 carcinoma cells per area were counted. Protein expression was assessed according to the immunoreactivity score (IRS) [26]. The score of every section is the average value of the five areas.
Materials and methods Statistical analysis Study patients and tissues In this study, 169 formalin-fixed, paraffin-embedded tissues of invasive breast cancer from May 2007 to June 2008 were obtained from the surgical pathology archive of the Qilu Hospital of Shandong University. There were survival data on 131 of the 169 patients with a median follow-up of 48 months. The histological grading of invasive breast cancer was performed using the modified Bloom-Richardson scoring system [23] and a three-tier grading system World Health Organization-based system modified by Fang and Thomas [24], respectively. Breast cancer subtypes were previously analyzed for the expression of immunohistochemical markers and defined as luminal-A cancer, luminal-B cancer, HER2positive cancer, and triple-negative cancer according to Perou et al [1].
Tissue microarray construction A total of eight tissue microarrays containing two cores of each sample were constructed from formalin-fixed, paraffinembedded invasive carcinomas and adjacent histological normal epithelium. The tissue microarrays were produced with the use of the MTA-1 manual tissue arrayer (Beecher Instruments, Woodland, CA, USA) as described [25].
The follow-up period was defined as the time from surgery to the last observation for censored or death for complete observations. Overall survival was defined as the time between the date of the primary surgery and the date of death or December 2012. Correlation between β-catenin expression and different molecular subtypes was determined using chi-square analysis. Survival curves were plotted by using the Kaplan-Meier method, and the differences between survival curves were compared by means of the log-rank test. Statistics were analyzed using SPSS 18.0 (Chicago, IL, USA). P0.05
Normal expression n (%)
Aberrant expression n (%)
Total
19 (44.19) 23 (35.94) 10 (41.67) 8 (21.05) 60 (35.50)
24 (55.81) 41 (64.06) 14 (58.33) 30 (78.95) 109 (64.50)
43 64 24 38 169
Kaplan-Meier overall survival curves were generated to assess prognostic ability of β-catenin. Of the 169 patients with invasive breast cancer in our cohort, we had data on overall survival on 131 of them with a median follow-up of 48 months. Those patients with aberrant β-catenin expression had a significantly reduced overall survival in the entire cohort and in each of the different molecular subtypes (Fig. 2a–e).
Discussion The role of Wnt/β-catenin signaling in human tumors has been supported by many studies, but to our knowledge, the exact role in breast cancer remains unclear. The possible explanations are these studies did not categorize the βcatenin subcellular localization and molecular subtypes. We therefore evaluated β-catenin expression in a cohort of invasive breast cancers with known patient phenotypes and outcome. Immunohistochemical studies of β-catenin in breast cancer have shown mixed results in terms of subcellular localization. Earlier reports focused on the loss or reduction of membranous expression of β-catenin [20, 29–32], but recent studies have demonstrated positive cytoplasmic/nuclear expression of β-catenin in breast cancer which is considered to be indicative of Wnt pathway activation [19, 27, 28, 33, 34]. In our study, β-catenin expression is located mainly in the membrane in normal cells, which is consistent with the previous results [31, 32], and β-catenin cytoplasmic expression in invasive breast
Tumor Biol.
Fig. 2 Aberrant β-catenin expression is associated with poor survival independent of molecular subtype. Kaplan-Meier overall survival curves are presented according to expression of β-catenin for the entire cohort (a),
luminal-A (b), luminal-B (c), HER2-positive (d), and triple-negative (e), respectively
Tumor Biol.
cancer is higher than that in normal tissue. Further studies with more sophisticated and in situ assessments of β-catenin protein levels may be warranted. Numerous prognostic factors have been evaluated in breast cancer patients to predict clinical outcome; furthermore, they are thought to be important in finding molecular mechanisms of abnormal tumor proliferation and potential targets for therapeutic intervention. There are multiple lines of evidence that suggest an important role for β-catenin in breast cancer. A recent study, which showed patients who had high coexpression of β-catenin and p53 had a significantly worse outcome, has demonstrated that a combined analysis of multiple markers, notably β-catenin and p53, may enhance the prognostic capabilities compared with individual markers [35]. In our study, β-catenin expression in a large series of invasive breast cancinomas is aberrant, which expands on the possibility that activation of signaling via the Wnt pathway is an important component of invasive breast cancinomas [14–16]. In an attempt to determine whether it was specifically activated in any molecular subtypes, we compared the expression of β-catenin in the four molecular subtypes. While some studies have demonstrated that the expression of β-catenin is significantly different in the four molecular subtypes and is enriched in triple-negative subtype [21, 28, 32, 34], we are unable to detect the difference of β-catenin expression in the four molecular subtypes. Furthermore, our results have shown that aberrant β-catenin expression is significantly associated with adverse outcome not only in the entire cohort but also in each of the different molecular subtypes, which suggests βcatenin may identify a subset of patients within each molecular subtype who have an even worse outcome. β-catenin together with molecular subtype might be helpful in identifying patients who might benefit from early systemic treatment. Several studies have showed Wnt/β-catenin activation is an important feature of triple-negative breast cancers and is predictive of worse overall survival [21, 28, 32, 34], while the recent evidences indicate that Wnt/β-catenin activation leads to HER2mediated breast cancer progression [36, 37] and is a potential mechanism involved in trastuzumab resistance in HER2overexpressing breast cancers [38]. As for luminal subtype, there is also data supporting Wnt/β-catenin signaling is involved in acquired tamoxifen resistance [39, 40]. The role of the Wnt/βcatenin pathway is still inconclusive in invasive breast cancer. This is not surprising because of the complexity of this molecular pathway and crosstalk between other signaling pathways. In conclusion, β-catenin is a valuable biomarker in predicting the prognosis, and its aberrant expression indicates poor outcome of invasive breast cancer. The precise mechanism between adverse outcome and Wnt/β-catenin pathway activation is still unknown. Through further understanding of the role of Wnt/β-catenin signaling activation, it is possible that β-catenin would be a potential therapeutic target for breast cancer.
Acknowledgments This study was supported by grants from the Shandong Province Science and Technology Development Projects (2013GSF11839) and Independent Innovation Foundation for Universities and Colleges in Jinan City (201311023). Conflicts of interest None.
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