|Year : 2021 | Volume
| Issue : 1 | Page : 38-46
|“Switch of E-Cadherin to N-Cadherin expression in different molecular subtypes of breast invasive duct carcinomas and its correlation with clinicopathological features”
Mayada S Farrag1, Abeer H Anter2, Nesrine S Farrag3, Afaf T Ibrahiem4
1 Department of Pathology, Faculty of Medicine, Port Said University, Port Said, Egypt
2 Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
3 Department of Community Medicine and Public Health, Faculty of Medicine, Mansoura University, Mansoura, Egypt
4 Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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|Date of Submission||26-Nov-2019|
|Date of Decision||09-Feb-2020|
|Date of Acceptance||07-Jun-2020|
|Date of Web Publication||8-Jan-2021|
| Abstract|| |
Background: In breast cancer, metastasis and recurrence is the main culprit in treatment failure. This study aimed to explore the role of E-cadherin/N-cadherin Switch in progression, spread and metastasis in breast invasive duct carcinoma. Materials and Methods: A cross-sectional study on 118 formalinfixed paraffinembedded mastectomy specimens of invasive breast duct carcinoma. Primary antibodies for E-cadherin (monoclonal, clone HECD-1; Zymed Laboratories; dilution 1:600) and N-cadherin (monoclonal, clone 3B9; Zymed Laboratories, Inc., Montrouge, France; dilution 1:200) were applied for all cases. The study revealed that E-cadherin high expression was significantly associated with advanced TNM clinical stage (P = 0.021), and nodal metastasis (P < 0.001). High expression of N-cadherin was significantly positively correlated with tumor sizes (P < 0.00), advanced clinical stage (P < 0.00), and nodal metastasis (P < 0.008). Mean OS was 39.99 months in cases with negative expression versus 41.8 months in cases with positive expression. Mean DFS in cases with positive E. cadh expression was 41.89 months was higher than mean DFS in cases with negative E. cadh expression which was 40.52 months, but it showed no statistical significance (P = 0.57). Conclusions/Significance: This study demonstrated that loss of E-cadherin and gain of N-cadherin promotes invasion, migration, and metastasis in invasive ductal carcinoma cells. Importantly, these findings may exploit new cancer therapies using N-cadherin antagonists.
Keywords: Breast carcinoma, cadherins, prognosis, survival
|How to cite this article:|
Farrag MS, Anter AH, Farrag NS, Ibrahiem AT. “Switch of E-Cadherin to N-Cadherin expression in different molecular subtypes of breast invasive duct carcinomas and its correlation with clinicopathological features”. Indian J Pathol Microbiol 2021;64:38-46
|How to cite this URL:|
Farrag MS, Anter AH, Farrag NS, Ibrahiem AT. “Switch of E-Cadherin to N-Cadherin expression in different molecular subtypes of breast invasive duct carcinomas and its correlation with clinicopathological features”. Indian J Pathol Microbiol [serial online] 2021 [cited 2022 May 26];64:38-46. Available from: https://www.ijpmonline.org/text.asp?2021/64/1/38/306542
| Introduction|| |
Worldwide, breast cancer is the most common malignancy in women. The prognosis for the cancer in women varies widely, some can live for long periods as normal women and others suffer from short life span, mainly due to metastasis and recurrence.
Metastasis is a key event in invasive carcinoma in which tumor cells must detach from the primary tumor, invade the basement membrane, penetrate the underlying stroma, and mix with stromal cells and further spread through the blood and lymphatics to remote organs.,
When epithelial cells lost its morphological characters and change to mesenchymal cells [Epithelial mesenchymal transition (EMT)]. This is the cornerstones that lead to the loss of E-cad expression or function and augment the aggressive and migratory propensity of malignant cells.
Cadherins consist of a family of transmembrane glycoproteins that enhance calcium-dependent homotypic cell–cell adhesion and maintain normal tissue architecture. Cadherin family includes P-, N- and R-cadherins.
Loss of E-cadherin–mediated adhesion has an important role in the transition of epithelial tumors from a benign to an invasive state; this loss is associated by high expression of N-cadherin that raised the possibility of its contribution to the invasive phenotype., Additionally, N-cadherin is expressed in endothelial cells and enhances the evolution and steadiness of normal vessels and tumor-associated angiogenic vessels. Large body of evidence points that N-cadherin can be a potential therapeutic target in cancer.
Loss of epithelial and gain of mesenchymal phenotype is important step that result in increased tissue mobility and invasion., This transition is attributed to cadherin switching E- to N-cadherin and other EMT inducers.,,
In this study, we try to explore the variable expression of E- and N-cadherins in different molecular subtypes of invasive duct carcinoma of breast and their relations to other clinical and pathological parameters and our patient's outcomes.
| Materials and Methods|| |
Review of recorded data from patient's files with operable invasive breast duct carcinoma attended to Nuclear Medicine Department, Oncology Centre, and University Hospital between 2013 and 2017 were analyzed for all clinical and pathological data including size, multiplicity, histological type, histological grade as regard to the modified scoring system of the Bloom–Richardson, lymphovascular or perineural invasion, LN metastases (N), metastasis (M), and TNM staging Also, we reviewed the clinical outcomes in the form of disease free survival (DFS) and overall survival (OAS).
We carried out this cross-sectional study in on 118 formalin-fixed paraffin-embedded mastectomy specimens of invasive breast duct carcinoma. The cases were chosen randomly from archives of surgical pathology lab at Oncology Center, Mansoura University. Patients were only eligible for this study if there are availability of paraffin blocks suitable for immunohistochemistry and adequacy of collected clinical data. Specimens from patients who received preoperative chemotherapy for invasive breast carcinoma were excluded. The work was being performed in agreement with the rules in the Declaration of Helsinki and was agreed by the local Medical and Bioethics committee of Mansoura University. An informed consent of the patients was applicable in the present study.
Sections were cut from paraffin-embedded tissue blocks at 4 μm, and deparaffinized it with xylene, then rehydrated with graded alcohols. The primary antibodies included antibodies for CK5/6 (mouse monoclonal, clone AE1/AE3, Dako, Denmark), Ki-67 (rabbit PAb, clone MIB-1, Neo Markers, USA), EGFR (mouse monoclonal, Clone 111.6, Neo Markers, USA), E-cadherin (monoclonal, clone HECD-1; Zymed Laboratories; dilution 1:600) and N-cadherin (monoclonal, clone 3B9; Zymed Laboratories, Inc., Montrouge, France; dilution 1:200). We used all of the antibodies according to manufacturer instructions. We made simultaneously positive and negative controls with test slides.
We performed antigen retrieval with heat in target retrieval solution pH 6.0 for estrogen receptors (ERs), progesterone receptors (PRs), HER2, Ki-67, E-cadherin, and N-cadherin, high pH for CK5/6 and enzyme digestion with 0.05% protease K for 30 min at 37 for epidermal growth factor receptor (EGFR). Primary antibodies for ER (rabbit monoclonal, Clone SP1, Cell Marque, USA), PR (mouse monoclonal, clone PgR636, Dako, Glostrup, Denmark), and HER2/neu (mouse monoclonal, clone CB-11, cell marque, USA) were used as a usual routine clinical diagnostic procedure.
Reviewing immunstaining for ER, PR, and HER 2neu. More than 1% of tumor nuclei were considered positive ER and PR stains For HER2, it was considered negative with a score of 0 and +1. It was considered positive with a score of +3 with strong complete membranous staining in at least 10% of tumor cells. We excluded cases of score 2+ as they require fluorescence in situ hybridization assay to confirm HER2 amplification. We considered EGFR stain positive if any cytoplasmic and/or membranous staining in tumor cells. We considered CK5/6 stain positive with any cytoplasmic and/or membranous staining in tumor cells. Ki-67 staining was considered as low or high using a 14% threshold.
According to the results of ER, PR, HER2, EGFR, CK5/6, and Ki-67, we classified tumors as luminal A (ER+ and/or PR+, HER2–, and Ki-67 <14% regardless the results of EGFR and CK5/6); luminal B either luminal B/HER2 negative (ER+ and/or PR+, HER2 – and Ki-67 ≥14%, regardless the results of EGFR and CK5/6) or luminal B/HER2 positive (ER+ and/or PR+, HER2+, and Ki-67 ≥14% regardless the results of EGFR and CK5/6); HER2 enriched (HER2+ and ER–/PR–); basal-like (ER–, PR–, HER2–, CK5/6+, and/or EGFR+); and unclassified (ER–, PR–, HER2–, EGFR–, CK5/6–).
The staining for E-cadherin and N-cadherin expression were membranous. The evaluation was based on the intensity of staining, the portion of the circumference of the cytoplasmic membrane stained and the percentage of cells exhibiting membranous staining. The tumor was considered negative (0) if no membranous staining was identified weak (1+) if faint staining involving a portion of the circumference of the cytoplasmic membrane in at least 10% of neoplastic cells; positive (2+) if moderate to definitive staining of the membrane over 100% of the cytoplasmic circumference in at least 10% of neoplastic cells; positive (3+) if strong positive staining of the membrane over 100% of the cytoplasmic circumference in at least 10% of neoplastic cells. For practical and statistical purposes, we grouped the weakly positive and negative cases together. Cases graded as moderate and strongly positive were considered positive tumors.
We performed our statistics by Chi-square and Fisher's exact tests to evaluate association between hyalouronan expression and other clinicopathological and histological parameters using SPSS18.0 software (IBM Inc, Chicago). We analyzed survival data using Kaplan–Meier test. We calculated overall survival time from the time of diagnosis to death. The disease-free survival (DFS) is defined as the time from time of primary surgery up to first recurrence or metastases. Survival curves were compared using the log-rank test. For multivariate analysis, we did Cox proportional hazard models. A two-tailed P ≤ 0.05 was considered statistically significant in all.
| Results|| |
Clinicopathological features of all breast carcinoma cases
Clinicopathological features of 118 cases of invasive breast carcinoma were summarized in [Table 1]; 82 (69.5%) of cases were postmenopausal, IDC nos represent 83% (98 cases), 20 (17%) were other variants. Regarding size, 67 (56.8%) were T2, 38 (32.2%) were T3, 10 (8.5%) were T1, only 3 cases (2.5%) were T1. Regarding molecular subtype of the involved cases; 43 (36.4%) were luminal A subtype, 32 (27.1%) were luminal B, and Her2neu overexpression was recorded in 9 (7.6%), the remaining 11 (9.3) cases were unclassified.
Five 5 (4.2%) were grade I, 87 (73.7%) were grade II, 26 (22.0%) were grade III. Necrosis was detected in 20 (16.9%). Lymphovascular emboli was detected in 21 (17.8%), and perineural invasion in one case only. Lymphnode involvement was noticed in 86 (72.9%). TNM stage (I&II) was detected in 51 (43%) while advanced stage (III) was in 67 (57%). Regarding hormonal expression in the studied breast cancer cases, 57 (48.3%) were ER positive, 63 (53.4%) expressed PR. Her2neu was positive in 22 (18.6%).71 (60.2%) cases showed less than 14% Ki67 proliferation while 47 (39.8%) showed more than 14%.
Clinicopathological features of breast carcinoma in relation to E-cadherin expression
Based on [Table 2], E-cadherin was expressed in 77 (56.8) of breast carcinoma cases. Regarding tumor size, E cadherin was expressed in 61% of T1 and T2, while was expressed in 48% in T3 and T4 but with no statistical significance (P = 0.167) [Figure 1].
|Table 2: Clinical features of breast carcinoma in relation to E-cadherin expression|
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|Figure 1: IHC staining of invasive duct carcinoma of breast showed strong membranous staining for E-cadherin in photo A ×200, moderate staining in photo B ×200 and scattered weak positive cells staining in photo C × 00. N -cadherin IHC showed strong membranous staining in photo D X200, moderated staining in photoEX200 and negative staining in photo FX200|
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E-cadherin high expression was significantly associated with advanced TNM clinical stage (P = 0.021), and nodal metastasis (P < 0.001). No significant association to age, grade, histologic type, perineural invasion, lymphvascular emboli, intraduct component or necrosis.
E-cadherin was expressed in 56% of low proliferative tumor (<14%) compared to 57% of highly proliferative tumor (<14%) with no significant statistical difference (P = 0.222). 59.6% of Her2neu-negative breast carcinoma expressed E-Cadherin while 22.2 of Her2neu-positive cases expressed E-cadherin.
N-cadherin expression in breast carcinoma and correlation to other clinicopathologic features
N-cadherin was expressed in 71 cases (60.2%). Based on [Table 3], N-cadherin high expression was significantly associated with large tumor sizes [62.5% of T3 and T4 are positively expressed N-cadherin compared to 56.5% of T2, and T3 (P < 0.00)]. N-cadh was detected in 70.8% of advanced TNM stage with statistical significance (P < 0.00). Also, N-cadherin expression was significantly associated with nodal metastasis (P < 0.008). No significant association to age, grade, histologic type, perineural invasion, lymphvascular emboli, intraduct component or necrosis. In relation to hormonal, Her2neu expression and molecular subtyping, no significant associations were recorded [Figure 1].
|Table 3: Clinical features of breast carcinoma in relation to N-cadherin expression|
Click here to view
Relationship among E-cadherin and N-cadherin in IDCs (Cadherin Switch) In studied cases
As reported in [Table 4], 24 cases expressed E-cadh but not expressed N-cadh, 28 cases lost E cadh and expressed N cadherin, 43 cases co-expressed the two cadherins while only 16 cases showed no expression of both markers. Pearson Chi-Square test showed weak correlation between expressions of the two markers (0.057) with no statistical significance (P = 0.811).
|Table 4: Relationship between E cadherin and N cadherin in studied cases|
Click here to view
Correlation of E-cadherin and N-cadherin expression with survival
A univariate analysis was performed to evaluate the impact of E-cadherin and N-cadherin expression on patient survival. Kaplan–Meier survival curves were constructed, followed by the log-rank test.
Overall survival results
Mean OS was 39.99 months in cases with negative and low expression versus 41.8 months in cases with positive expression, 33.8% of patients with negative E-cadherin tumors died of disease compared with 16.4% of patients with positive E-cadherin tumors (P = 0.45). No significant difference was found between positive and negative E-cadh expression in relation to poor overall patient survival [Diagram 1].
N. cadherin expression
Mean OS was 43.63 months in cases with negative expression versus 39.94 months in cases with positive expression, 12.8% of patients with negative E-cadh tumors died of disease compared with 22.5% of patients with positive E-cadh tumors (P = 0.45) [Diagram 1].
Disease free survival (DFS)
Mean DFS in cases with positive E-cadherin expression was 41.89 months. It was higher than mean DFS in cases with negative E-cadherin expression which was 40.52 months, but it showed no statistical significance (P = 0.57) [Diagram 1].
No significant difference was found between positive and negative N-cadherin expression regarding DFS. Mean DFS in cases with positive N-cadherin expression was 38.92 months. It was lower than mean DFS in cases with negative N-cadherin expression which was 43.1 months, but it showed no statistical significance (P = 0.12) [Diagram 1].
| Discussion|| |
Epithelial-to-mesenchymal transition (EMT) is a highly dynamic manner, through which epithelial cells can convert into a mesenchymal phenotype.,,, During EMT, E-cadherin expression is markedly decreased to near-zero level, then E-cadherin-to-N-cadherin switch is mounted and N-cadherin is expressed with other EMT-related markers as vimentin, smooth muscle actin (SMA), desmin and fibronectin.,
The present study assess the expression of E- and N-cadh in different molecular subtypes of invasive duct carcinomas and its correlation with clinicopathological features aiming for more understanding of the underlying mechanisms in breast invasive ductal carcinoma and its impact on patient clinical outcomes in different molecular subtypes.
E-cadherin expression change in breast cancer remains rather controversial. Some authors have demonstrated correlations between reduced E-cadherin expression and lymph node metastasis in breast cancer,,,, whereas others have failed to determine the existence of a relationship between E-cadherin expression and patients survival.,
In our analysis, E-cadherin was expressed in 67 (56.8%) of breast carcinoma cases. These results are in agree with Kowalski et al. who reported 55% of their study cases had positive (normal) E-cadherin expression and 45% had irregular E-cadherin protein expression. But our results were less than Moll et al. (79% of E-cadherin positivity in IDC cases) and also less than those of Howard et al. (84% positivity) and Gamello et al. (94% positivity).
We found a significant correlation between loss of E-cadherin expression and advanced TNM clinical stage (P < 0.001), and nodal metastasis (P = 0.021); 86% of non-metastatic breast carcinoma expressed E-cadherin but only 40% of breast cancer cases associated with lymph nodes metastasis. This is consistent with results that reported by Yang et al. Other revisions have reported that a loss of E-cadh expression in breast carcinoma is strictly related to invasion and metastasis. These significant associations suggest that loss of E-cadherin expression assists aggressive tumor growth by depriving the cell from a support structure for cells to adhere, thus accelerating invasion and metastasis.
In this study, E-cadherin expression showed no significant association with histological tumor grade in agreement with results in studies carried by Yang et al. and Howard et al. However, a reported association was recorded in other studies.,
Molecular grouping of breast cancer is an important predictive factor, and also is important for better designing of treatment. However, it is hypothesized that the molecular profile of breast cancer is not stable throughout tumor progression. Moreover, Falck et al. found that a shift in molecular subtype between primary tumor and metastatic lymph node occurs.,
Correlation of E-Cadherin expression with molecular types is not so well known. Chekhun et al. showed that the aggressive behavior and metastasis in basal and luminal subtypes are strongly dependent on expression of E-cadherin.
Our study showed loss of E-Cadherin expression is more in triple negative basal subtype compared to luminal B subtype, and Her2 neu enriched subtype (65.2%, 59.4%, 33.3% respectively). Our results are consistent with the results of Liu J et al., 2017 who recorded that loss of E-cad expression was more in TNBC type than tumors with non-TNBC molecular subtypes.
High tumorigenicity of cells of the basal subtype is related to weakening of adhesive contacts that are caused by abnormalities of E-cadherin expression, so loss of E-cadherin expression may be considered a reliable predictor for early invasion and metastasis of TNBC and may be a potential therapeutic target for treating these aggressive invasive breast cancers.,,
The loss of E-cadherin expression in breast cancer is frequently associated with poor prognostic features including metastatic lymph node status, tumor recurrence, low grade of differentiation, and advanced stage of tumor as reported by Gould et al. So little colony-forming activity of the luminal subtype is connected with augmented adhesive properties of these cells due to a great level of E-cadherin expression.
Cadherin switching refers to a switch from expression of E-cadherin to expression of N-cadherin, but also includes situations in which E-cadherin expression levels do not change significantly but the cells turn on (or increase) expression of N-cadherin.,
N-cadherin increases the migratory and invasive capacity of tumor cells, regardless of E-cadherin expression. Thus, the attainment of N-cadherin is suggested to be a serious step in epithelial cancer progression and metastasis.
Many studies investigated the role of N-cadherin in breast cancer cell lines, and concluded its role in cell motility, migration, and invasion. However, little studies were carried on paraffin embedded cancer tissue and correlated the N-cadherin expression in breast cancer to clinical outcomes and molecular subtypes.
In the current study, cadherins switch occurred in 71 (60.2%) of invasive ductal breast carcinoma, including 43 cases co-expressed the two cadherins. N-cadh was detected in 70.8% of advanced TNM clinical stage with statistical significance (P < 0.00). Also, N-cadherin expression was significantly associated with nodal metastasis (P < 0.008). Similar results were reported by El-Moneim, and Zaghloul, however, in contrast to us they recorded a significant correlation between E-cadherin and N-cadherin expression.
Also, in 2005, Nagi et al. found that N-cadherin was significantly related with invasive micropapillary tumors (P = 0.033) compared to E-cadh (P = 0.171), and concluded that N-cadherin is associated with tumor aggressiveness and metastatic potential. Other studies have reported that there was no significant association between N-cadherin expression and both nodal status, and TNM stage.
Hazan et al., suggested that overexpression of N-cadherin in breast carcinoma correlates with invasiveness as a result of N-cadherin-mediated interactions between cancer cells and stromal cells. Besides, others put amplified level of N-cadherin as an indicator of continuing EMT and tumor evolution.
Here, we found N-cadherin expression was not significantly correlated to tumor grade. This opposes preceding results that described a connotation between N-cadherin expression and high tumor grade.
In other organs cancers rather than breast carcinoma as in prostate and urothelial tumors, and pancreatic cancer, overexpression of N-cadherin is related to the invasion, metastasis, and poor outcomes., It was also frequent with postoperative recurrence in hepatocellular carcinoma. On the other side, down-regulation of N-cadherin in glioblastoma, ovarian carcinoma, and osteosarcoma are linked to poor clinical outcomes.,,
From these previous studies and literatures, combined assessment for E-cadherin and N-cadherin might be more appreciated in prognostic evaluation of breast carcinoma., This Cadherin switch is related with increased migratory and invasive behavior, bad patient prognosis and worse overall survival.,
In the current study, no significant change was found between either loss of E- cadh or positive N-cadh expression and DFS and poor overall patient survival. But on considering that the presence of axillary lymph node metastases is important predictor for poor disease-free as well as overall survival predictor. In this study, cadherin switch is correlated to lymph node metastasis, so it could be considered predictors for poor prognosis and patient outcomes.
In previous studies done by Nagi et al. and Qian, et al., N-cadherin expression in ductal breast carcinomas was correlated with tumor progression (larger tumor size, positive L.Ns and higher metastatic risk). Our results are similar, but in addition we correlated N-cadherin expression with patient prognosis. We found that mean DFS in cases with positive E-cadherin expression was 41.89 months compared to 40.52 months in cases with negative E-cadherin expression. Also, mean DFS in cases with positive N-cadherin expression was 38.92 months compared to 43.1 in cases with negative N. cadherin expression. Other studies identified N-cadherin as an original prognostic indicator of progression in superficial urothelial tumors and prostate carcinoma.
More studies are in agreement with us by reporting the poor prognostic effect of overexpression of N-Cadherin on overall survival and disease-free survival, with a more evident tendency for relapse and metastasis although the P values were not significant,, thus our results together with further future studies using molecular techniques could prove that N-cadherin is a possible target for either diagnosis or treatment of breast cancer.
In conclusion, this study demonstrated that loss of E cadherin and expression of N-cadherin promotes invasion, migration, metastasis (local, lymph nodal and distant) in invasive ductal carcinoma cells. Importantly, these findings may exploit new cancer therapies using N-cadherin antagonists.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Mayada S Farrag
Department of Pathology, Port Said Faculty of Medicine, Port Said
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4]
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