Expression of classical NF‐κB pathway effectors in human ovarian carcinoma

Darb‐Esfahani S, Sinn B V, Weichert W, Budczies J, Lehmann A, Noske A, Buckendahl A‐C, Müller B M, Sehouli J, Koensgen D, Györffy B, Dietel M & Denkert C
(2010) Histopathology 56. 727–739
Expression of classical NF‐κB pathway effectors in human ovarian carcinoma Aims: Functional studies have demonstrated that nuclear factor (NF)‐κB promotes tumour progression in ovarian cancer cells. However, surprisingly little is known of the expression of effectors of the NF‐κB pathway in human ovarian cancer in vivo. Methods and results: Immunohistochemistry and in situ hybridization revealed that in a cohort of 85 primary ovarian carcinomas, total p65 expression was inversely correlated to nuclear and cytoplasmic phospho‐IκBα (P = 0.002 and P = 0.05, respectively), and IκBα mRNA expression (P = 0.032). In contrast, phospho‐p65 expression was paralleled by the expression of nuclear (P = 0.027) and cytoplasmic phospho‐IκBα (P = 0.01). Total p65 expression was an adverse prognostic factor for overall survival (P = 0.018). In contrast, total IκBα and phosphorylated nuclear and cytoplasmic IκBα expression were favourable prognostic markers (P = 0.001, P = 0.031, P = 0.001, respectively). Cytoplasmic phospho‐IκBα expression remained a significant prognostic factor on multivariate analysis (P = 0.010). In cultured, stimulated OVCAR‐3 ovarian cancer cells the cytoplasmic retranslocation of p65 was delayed by inhibition of the nuclear membrane transporter chromosomal region maintenance/exportin1 protein (CRM1). A positive association of p65 and CRM1 expression was demonstrated in ovarian cancer tissue (P < 0.0001). Conclusions: Total and phosphorylated IκBα protein expression might serve as markers for NF‐κB activation in human ovarian carcinoma. Cytoplasmic localization of p65 may be related to deregulated nucleocytoplasmic transport in carcinomas overexpressing CRM1.     

LC3A‐Positive “Stone‐Like” Structures Predict an Adverse Prognosis of Gastric Cancer

Microtubule‐associated protein light chain 3 (LC3A) is a reliable marker of autophagy that displays three distinct patterns of immunohistochemical staining in solid tumors: diffuse cytoplasmic staining, juxtanuclear staining, and staining of “stone‐like” structures. These three patterns have a different prognostic significance in many solid tumors, but little is known about their influence in gastric cancer (GC). This study was a retrospective analysis of 188 GC patients from stages I to IV. The pattern of LC3A expression was examined in tumor and nontumor tissues by immunohistochemistry. Then, the association between the pattern of LC3A expression in GC and the prognosis was investigated by Kaplan‐Meier analysis and the Cox proportional hazards model. Two distinct patterns of LC3A immunostaining (diffuse cytoplasmic expression and “stone‐like” structures) were observed in GC tissues. LC3A‐positive “stone‐like” structures were found only in the tumors, and the number of such structures was correlated with both the tumor type and tumor stage. In addition, a high number of LC3A‐positive “stone‐like” structures was closely associated with an increased risk of recurrence after radical resection of stages I–III cancer (P < 0.001; HR = 0.205) and was associated with a lower overall survival rate for stage IV cancer (P < 0.001; HR = 0.364). Taken together, our data demonstrate that LC3A‐positive “stone‐like” structures can be used as an independent biomarker for an adverse prognosis of GC, suggesting that “stone‐like” structures are correlated with the malignancy of this disease. Anat Rec, 297:653–662, 2014. © 2014 The Authors The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology Published by Wiley Periodicals, Inc.     

Autoimmune Response to IGF2 mRNA‐Binding Protein 2 (IMP2/p62) in Breast Cancer

The purpose of this study was to understand the autoimmune response and immunogenicity of a tumour‐associated antigen IMP2/p62 in breast cancer. Autoantibody responses to IMP2/p62 were evaluated by enzyme‐linked immunosorbent assay (ELISA), Western blotting and indirect immunofluorescence assay in sera from patients with breast cancer, benign breast tumour and normal human individuals. Immunohistochemistry (IHC) study with breast cancer tissues was also performed to analyse protein expression of IMP2/p62. The results have demonstrated that IMP2/p62 can induce a relatively higher frequency of autoantibody response in breast cancer (14.3%, 7/49) compared to patients with benign breast tumour (5.6%, 2/36) and normal individuals (2.2%, 1/44). The frequency of IMP2/p62 expression in breast cancer tissues was significantly higher than that in normal tissues (P < 0.01). The data suggest that autoantibody against IMP2/p62 may be a useful serum biomarker for early‐stage breast cancer screening and diagnosis.     

Increased staining for phosphorylated AKT and nuclear factor‐κB p65 and their relationship with prognosis in epithelial ovarian cancer

AKT plays an important role in malignant behavior of tumors. The purpose of the present study was to determine the expression of phosphorylated AKT (P‐AKT) and nuclear factor‐κB (NF‐κB) p65 and their association with clinicopathological parameters and prognosis in epithelial ovarian tumor. On immunohistochemistry 115 samples of ovarian tissue that included 68 specimens of epithelial ovarian cancer, 12 of borderline tumor, 24 of epithelial benign tumor and 11 of normal ovary, were evaluated. Sixty‐three patients with ovarian cancer were followed up from 7 to 68 months. The positive expression rate of P‐AKT and NF‐κB p65 were higher in epithelial ovarian cancer than in normal ovarian tissue (P < 0.01). Elevated P‐AKT or NF‐κB p65 expression was significantly correlated with late clinical stage (P < 0.05 and P < 0.01) and poor histological differentiation (both P < 0.01). P‐AKT expression was significantly correlated with NF‐κB p65 immunostaining (φ = 0.272, P < 0.05). Elevated expression of P‐AKT was negatively correlated with the survival of ovarian cancer patients, but it was not an independent prognostic factor after multivariate analysis. Overexpression of P‐AKT and NF‐κB p65 were involved in the carcinogenesis and metastasis of ovarian cancer. P‐AKT might contribute to the malignant transformation through NF‐κBp65 upregulation.     

Association of autophagy status with amount of Fusobacterium nucleatum in colorectal cancer

Fusobacterium nucleatum (F. nucleatum), which has been associated with colorectal carcinogenesis, can impair anti-tumour immunity, and actively invade colon epithelial cells. Considering the critical role of autophagy in host defence against microorganisms, we hypothesised that autophagic activity of tumour cells might influence the amount of F. nucleatum in colorectal cancer tissue. Using 724 rectal and colon cancer cases within the Nurses' Health Study and the Health Professionals Follow-up Study, we evaluated autophagic activity of tumour cells by immunohistochemical analyses of BECN1 (beclin 1), MAP1LC3 (LC3), and SQSTM1 (p62) expression. We measured the amount of F. nucleatum DNA in tumour tissue by quantitative polymerase chain reaction (PCR). We conducted multivariable ordinal logistic regression analyses to examine the association of tumour BECN1, MAP1LC3, and SQSTM1 expression with the amount of F. nucleatum, adjusting for potential confounders, including microsatellite instability status; CpG island methylator phenotype; long-interspersed nucleotide element-1 methylation; and KRAS, BRAF, and PIK3CA mutations. Compared with BECN1-low cases, BECN1-intermediate and BECN1-high cases were associated with lower amounts of F. nucleatum with odds ratios (for a unit increase in three ordinal categories of the amount of F. nucleatum) of 0.54 (95% confidence interval, 0.29–0.99) and 0.31 (95% confidence interval, 0.16–0.60), respectively (P_trend < 0.001 across ordinal BECN1 categories). Tumour MAP1LC3 and SQSTM1 levels were not significantly associated with the amount of F. nucleatum (P_trend > 0.06). Tumour BECN1, MAP1LC3, and SQSTM1 levels were not significantly associated with patient survival (P_trend > 0.10). In conclusion, tumour BECN1 expression is inversely associated with the amount of F. nucleatum in colorectal cancer tissue, suggesting a possible role of autophagy in the elimination of invasive microorganisms. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Synaptopodin‐2 suppresses metastasis of triple‐negative breast cancer via inhibition of YAP/TAZ activity

Triple‐negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, with a high incidence of distant metastasis; however, the underlying mechanism for this frequent recurrence remains unclear. Herein, we show that synaptopodin‐2 (SYNPO2), a putative tumour suppressor in aggressive cancer, is frequently downregulated in TNBC by methylation of the promoter of SYNPO2. Low expression levels of SYNPO2 correlated significantly with 5‐year metastatic relapse, and predicted poorer prognosis in breast cancer patients. Reintroduction of SYNPO2 inhibited the invasion and spontaneous metastasis of TNBC cells in vivo. Strikingly, downregulation of SYNPO2 is essential for the maintenance of stem cell‐like properties in TNBC cells, leading to efficient distant colonization and metastasis outgrowth. Moreover, we demonstrate that SYNPO2 inhibits the activities of YAP and TAZ by stabilizing LATS2 protein, and transduction of YAP‐S127A abrogates the repressive role of SYNPO2 in metastasis. Finally, immunohistochemical (IHC) analysis of breast cancer patient specimens indicated that the SYNPO2–LATS2–YAP axis is clinically relevant. These findings uncover a suppressive role of SYNPO2 in TNBC metastasis via inhibition of YAP/TAZ, and suggest that SYNPO2 might provide a potential prognosis marker and novel therapeutic strategy. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Expression of p16 and pRB in invasive breast cancer

We aimed to assess protein expressions of p16 and pRB in breast cancer and explore the clinicopathologic implications. Tissue microarray (TMA) was constructed with 406 cases of breast cancer. The cases were subgrouped into luminal A, luminal B, HER-2, and triple negative breast cancer (TNBC) based on the results of immunohistochemical stains for ER, PR, HER-2, and Ki-67 and fluorescent in situ hybridization (FISH) for HER-2. One hundred and sixty-eight cases were allocated to the subgroup luminal A; 87 cases to the luminal B; 32 cases to the HER-2; and 119 cases to the TNBC. The TNBC group showed the highest negative rate for p16, and the luminal B and HER-2 groups showed the highest positive rate for p16 (P < 0.001). Alteration of p16 was the highest in the luminal B and HER-2 groups, and pRB expression rate was the highest in the HER-2 group and lowest in the luminal A group. In addition, p16(+)/pRB(+) type was the most common in the luminal B group, p16(+)/pRB(-) in the luminal A group, and p16(-)/pRB(+) in the TNBC group (P < 0.001). Altered p16/pRB(+) and non-altered p16/pRB(+) type was the most common in the luminal B, and altered p16/pRB(-) and non-altered p16/pRB(+) type was the most common in the luminal A (P < 0.001). Alteration of p16 was correlated with higher Ki67 labeling index (LI) (P = 0.013), and p16 negativity was correlated with ER negativity (P = 0.002), PR negativity (P = 0.004), and higher Ki67 LI (P < 0.001). pRB positivity was correlated with PR negativity (P = 0.009), HER-2 positivity (P = 0.001), and higher Ki-67 LI (P < 0.001). In luminal group A, p16 alteration was correlated with shorter DFS in univariate analysis (P = 0.024). In conclusion, Expression rates of p16 and pRB differ according to the molecular subgroups of breast cancer and they subsequently correlate with clnicopathologic factors.     

Analysis of differentially expressed proteins between HER2 positive and triple negative breast cancer and their prognostic significance

Both triple negative breast cancer (TNBA) and HER2-positive breast cancer lack expression of estrogen receptor alpha (ER) and progesterone receptor (PR), while human epidermal growth factor receptor 2 (HER2) in TNBC is also negative. This study aimed to identify the differentially expressed proteins (DEPs) between TNBC and HER2-positive breast cancer and to improve understanding of their role in the prognosis of breast cancer. By analyzing the breast cancer data set in The Cancer Proteome Atlas (TCPA) database, 15 DEPs between TNBC and HER2-positive breast cancer were identified. GO and pathway enrichment analysis were performed on DEPs, and the protein–protein interaction (PPI) network was constructed. The overall survival (OS) analysis of the breast cancer protein dataset in the Kaplan-Meier plotter showed that low expression of ACC1 suggested a higher OS of HER2-positive breast cancer (HR = 5.34, P < 0.05) and TNBC (HR = 2.88, P < 0.05). And TNBC patients with high TBA1B (HR = 0.16, P < 0.01) or low INPP4B (HR = 3.47, P < 0.05) expression have a better prognosis. Our research provides new insights into the prognostic indicators of TNBC and HER2-positive breast cancer, which could be further studied.     

Stromal CD10 expression and relationship to the E‐cadherin/β‐catenin complex in breast carcinoma

Kim H‐S, Kim G Y, Kim Y W, Park Y‐K, Song J‐Y & Lim S‐J
(2010) Histopathology 56, 708–719
Stromal CD10 expression and relationship to the E‐cadherin/β‐catenin complex in breast carcinoma Aims: Previous investigations have indicated that stromal CD10 expression, and altered levels of both E‐cadherin and β‐catenin, are associated with the biological aggressiveness of human carcinoma. The aim was to evaluate stromal CD10 expression and the association of stromal CD10 with E‐cadherin and β‐catenin in breast carcinoma. Methods and results: The expression of CD10, E‐cadherin and β‐catenin was immunohistochemically analysed in tissue microarrays containing 104 cases of invasive ductal carcinoma (IDC) and 10 cases of ductal carcinoma in situ (DCIS). Stromal CD10 was detected in 49.5% (50/101) of the IDC. No immunoreactivity was identified in the stromal cells of normal breast, DCIS or intraductal components of IDC. Accumulation of the cytoplasmic β‐catenin was found in 87.0% (87/100) of the IDC. Stromal CD10 expression in IDC was significantly correlated with tumour size (P = 0.027), stage (P < 0.001) and histological grade (P = 0.006), the presence of nodal (P = 0.048) and distant (P = 0.015) metastases, oestrogen receptor‐negative status (P = 0.016), cytoplasmic β‐catenin accumulation (P = 0.031) and lower overall survival rate (P = 0.041). Conclusions: Stromal CD10 expression in IDC may constitute an important prognostic marker. Stromal CD10 expression with associated aggressive features might be related to aberrant β‐catenin expression.     

Anti‐nuclear antibodies in patients with breast cancer

To study the prevalence of anti‐nuclear antibodies (ANA) in breast cancer patients and its association with tumour characteristics. Ninety‐one patients with breast mass detected by image studies and assigned to conduct diagnostic biopsy and eventual surgical treatment were studied for demographical, tumour data and presence of ANA. Serum of positive ANA patients was screened for the extractable nuclear antigen (ENA) profile. As comparison, 91 healthy individuals matched for age and from the same geographical area were included. In this sample 72 of 91 (79·1%) had malignant lesions (83% ductal infiltrative carcinoma). ANA was positive in 44·4% of patients with malignant tumour and in 15·7% of those with benign lesions (malignant versus benign with P = 0·03). Controls had ANA positivity in 5·4%, and when compared with tumour samples showed P < 0·0001. The most common immunofluorescence pattern was a fine dense speckled pattern. In the ANA‐positive patients with malignant lesions, seven had positivity for ENA profile (three for anti‐RNP and anti‐Sm, one for just anti‐RNP, two for anti‐Ro and anti‐La e two for just anti‐La). It was not possible to associate ANA positivity with tumour histological characteristics or staging or with patient's age. A negative association of ANA with hormonal (oestrogen or oestrogen plus progesterone) receptor status was found (P = 0·01). In this sample, there was a high prevalence of ANA positivity in breast cancer patients with a negative association with the presence of hormonal receptors. More studies are needed to understand the real value of this finding.     

Study on the Autophagy of Prostate Cancer PC‐3 Cells Induced by Oridonin

To investigate the mechanism of oridonin (ORI)‐induced autophagy in prostate cancer PC‐3 cells, PC‐3 cells cultured in vitro were treated with ORI, and the inhibitory ratio of ORI on PC‐3 cells was assayed by 3‐4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide. The ultrastructural changes of the cells were observed under light microscope, scanning electron microscope (SEM), and transmission electron microscope (TEM). Acridine orange (AO) staining was used to observe the acidic vesicular organelles (AVOs). The level of autophagy‐related proteins, MAP1‐LC3, was detected by Western Blot, and RT‐PCR was used to detect the level of mRNA of beclin 1. After ORI treatment, the proliferation of PC‐3 cells was inhibited significantly in a concentration and time‐dependent manner. SEM examination revealed cellular shrinkage and disappearance of surface microvilli in ORI‐treated cells. Under TEM examination, the nuclei exhibited chromatin condensation and the appearance of a large number of autophagosomes with double‐membrane structure in cytoplasm. AO staining showed the existence of AVOs. The expression of LC3 and the mRNA level of beclin 1 was increased by ORI. Furthermore, autophagy inhibitor 3‐methyladenine reversed the increase of beclin 1 mRNA. The growth of PC‐3 cells was inhibited, and autophagy was induced by ORI, indicating ORI may have a potential antitumor effect. Anat Rec, 2012. © 2011 Wiley Periodicals, Inc.     

Expression of key hypoxia sensing prolyl‐hydroxylases PHD1, ‐2 and ‐3 in pancreaticobiliary cancer

Gossage L, Zaitoun A, Fareed K R, Turley H, Aloysius M, Lobo D N, Harris A L & Madhusudan S
(2010) Histopathology 56, 908–920
Expression of key hypoxia sensing prolyl‐hydroxylases PHD1, ‐2 and ‐3 in pancreaticobiliary cancer Aims: Tumour hypoxia is associated with an aggressive phenotype and resistance to chemotherapy and radiotherapy. The aim was to investigate whether key hypoxia sensing prolyl hydroxylases PHD1, PHD2 and PHD3 are dysregulated in pancreaticobiliary cancers, and to evaluate their potential clinical significance. Methods and results: Formalin‐fixed human pancreatic tissue from 120 consecutive patients undergoing pancreatic resections between June 2001 and June 2006 was constructed into tissue microarrays. Expression of PHD1, PHD2 and PHD3 was analysed using immunohistochemistry and correlated with clinicopathological variables and disease‐specific overall survival. PHD1, PHD2 and PHD3 were significantly overexpressed in pancreaticobiliary tumours compared with normal pancreatic ductal tissues (P = 0.03, P < 0.0001 and P < 0.0001, respectively). PHD3 expression in tumour tissue was associated with a trend towards worse overall disease‐specific survival in ampullary adenocarcinomas (P = 0.035) and pancreatic adenocarcinomas (P = 0.084). Absence of PHD1 expression was significantly associated with perineural invasion in pancreatic adenocarcinomas (P = 0.02) and a trend towards significance was also seen for absence of PHD2 expression in pancreatic adenocarcinomas (P = 0.04). Conclusions: Our results provide the first clinical evidence that PHD1, PHD2 and PHD3 may be involved in pancreaticobiliary tumorigenesis.     

The B‐cell‐activating factor signalling pathway is associated with Helicobacter pylori independence in gastric mucosa‐associated lymphoid tissue lymphoma without t(11;18)(q21;q21)

We previously reported that activation of the B‐cell‐activating factor (BAFF) pathway upregulates nuclear factor‐κB (NF‐κB) and induces BCL3 and BCL10 nuclear translocation in Helicobacter pylori (HP)‐independent gastric diffuse large B‐cell lymphoma (DLBCL) tumours with evidence of mucosa‐associated lymphoid tissue (MALT). However, the significance of BAFF expression in HP independence of gastric low‐grade MALT lymphomas without t(11;18)(q21;q21) remains unexplored. Sixty‐four patients who underwent successful HP eradication for localized HP‐positive gastric MALT lymphomas without t(11;18)(q21;q21) were studied. BAFF expression was significantly higher in the HP‐independent group than in the HP‐dependent group [22/26 (84.6%) versus 8/38 (21.1%); p < 0.001]. Similarly, BAFF receptor (BAFF‐R) expression (p = 0.004) and nuclear BCL3 (p = 0.004), BCL10 (p < 0.001), NF‐κB (p65) (p = 0.001) and NF‐κB (p52) (p = 0.005) expression were closely correlated with the HP independence of these tumours. Moreover, BAFF overexpression was significantly associated with BAFF‐R expression and nuclear BCL3, BCL10, NF‐κB (p65) and NF‐κB (p52) expression. These findings were further validated in an independent cohort, including 40 HP‐dependent cases and 18 HP‐independent cases of gastric MALT lymphoma without t(11;18)(q21;q21). The biological significance of BAFF signalling in t(11;18)(q21;q21)‐negative lymphoma cells was further studied in two types of lymphoma B cell: OCI‐Ly3 [non‐germinal centre B‐cell origin DLBCL without t(11;18)(q21;q21) cell line] and MA‐1 [t(14;18)(q32;q21)/IGH‐MALT1‐positive DLBCL cell line]. In both cell lines, we found that BAFF activated the canonical NF‐κB and AKT pathways, and induced the formation of BCL10–BCL3 complexes, which translocated to the nucleus. BCL10 and BCL3 nuclear translocation and NF‐κB (p65) transactivation were inhibited by either LY294002 or by silencing BCL3 or BCL10 with small interfering RNA. BAFF also activated non‐canonical NF‐κB pathways (p52) through tumour necrosis factor receptor‐associated factor 3 degradation, NF‐κB‐inducing kinase accumulation, inhibitor of κB kinase (IKK) α/β phosphorylation and NF‐κB p100 processing in both cell lines. Our data indicate that the autocrine BAFF signal transduction pathway contributes to HP independence in gastric MALT lymphomas without the t(11;18)(q21;q21) translocation. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Prolactin receptor expression as a novel prognostic biomarker for triple negative breast cancer patients

Prolactin receptor (PRLR) is a novel emerging prognostic biomarker in different cancers, especially in breast cancer. However, there is limited information about the association of PRLR expression and triple-negative breast cancers (TNBC) prognosis. In this study, 80 TNBC patients were evaluated for PRLR expression by immunohistochemistry. The correlation of PRLR expression with clinicopathological features, patient recurrence, and survival was investigated. PRLR expression was considered positive if >10% of tumor cells were stained. The Fisher's exact test was used to analyze PRLR expression relation with the clinicopathological parameters. Survival distribution was estimated by the Kaplan-Meier method. Positive immunoreactivity for PRLR was observed in 50 out of 80 (62%) specimens. Although expression of PRLR was associated with TNBC patients' stage, no-correlation was observed between its expression and tumor size, grade, lymph node status, and Ki-67 expression. In addition, patients with positive expression of PRLR exhibited lower recurrence (P = 0.0027) and higher overall survival (P = 0.0285) in comparison with negative expression group. In multivariate analyses, positive expression of PRLR was an independent prognostic marker for lower recurrence (P < 0.001) and higher overall survival (P < 0.001). Therefore, PRLR plays a crucial role in TNBC and has to be considered as an independent prognostic biomarker for TNBC patients.     

Expression patterns of stromal MMP‐2 and tumoural MMP‐2 and ‐9 are significant prognostic factors in invasive ductal carcinoma of the breast

Matrix metalloproteinases (MMPs) are matrix‐degrading enzymes that play a pivotal role in aggressive behaviours, such as rapid tumour growth, invasion, and metastasis, of several types of solid tumours. In particular, stromal MMP‐2 plays important roles in the progression of malignant tumours, but most clinical studies have focused on tumoural MMP‐2 and ‐9 expression, and not stromal MMP‐2 expression. One hundred and seventy‐seven cases diagnosed as invasive ductal carcinoma of the breast between 2000 and 2005 were included in this study. Expressions of tumoural MMP‐2 and ‐9 and stromal MMP‐2 were analysed by immunostaining on a tissue microarray. Subsequently, the associations between those results and various clinicopathological parameters were evaluated. Stromal MMP‐2 expression correlated significantly with clinicopathological parameters such as advanced T category, larger tumour size, high histological grade, tumour necrosis, ER‐ and PR‐negative, and HER‐2‐positive (all p < 0.05). In univariate and multivariate analyses, overall survival was linked with stromal MMP‐2 expression as well as dual expression of stromal MMP‐2 and tumoural MMP‐2 and ‐9 (all p < 0.05). Stromal MMP‐2 expression may play a crucial role in predicting aggressive clinical behaviour in breast cancer patients.     

Insulin growth factor receptor‐1 expression and loss of PTEN protein predict early recurrence in triple‐negative breast cancer

Iqbal J, Thike A A, Cheok P Y, Tse G M‐K & Tan P H
(2012) Histopathology  61, 652–659 Insulin growth factor receptor‐1 expression and loss of PTEN protein predict early recurrence in triple‐negative breast cancer Aims: Insulin‐like growth factor receptor‐1 (IGFR‐1) and its signalling axis promote tumorigenesis, metastasis, and resistance to existing forms of cancer therapy, and have become a major focus for the development of anticancer drugs. As oncological management options for triple‐negative breast cancers (TNBCs) are limited, there is potential for the rapid development of novel selective anticancer agents specifically targeting components of the PTEN–phosphoinositide 3‐kinase–AKT pathway, including the phosphorylated form of AKT (pAKT) and the tumour suppressor molecule PTEN. The aim of this study was to conduct immunohistochemical analyses to examine the levels of PTEN, IGFR‐1 and pAKT expression in TNBCs, and determine whether these levels correlated with poor prognosis in this subset of aggressive breast cancers. Methods and results: Immunohistochemistry was performed on paraffin‐embedded tumour tissues from a consecutive cohort of 144 female patients diagnosed with TNBC. Associations of IGFR‐1, PTEN and pAKT expression with clinicopathological parameters, disease‐free survival (DFS) and overall survival (OS) were evaluated. There were significant increases in IGFR‐1 expression (99%) and pAKT expression (92%) with concomitant loss of PTEN expression in the majority of cases (63%). Increased IGFR‐1 expression and loss of PTEN expression were associated with reduced OS and DFS, respectively. pAKT expression showed a strong correlation with basal‐like expression. Combinatorial immunophenotypic analyses showed that loss of PTEN expression with concomitant IGFR‐1 expression correlated with poor DFS. Conclusions: A high percentage of PTEN loss with overexpression of IGFR‐1 and pAKT in TNBC indicates the potential of these molecules for predicting early recurrence and/or as targets in the formulation of effective alternative therapy regimens.     

Higher expression of EpCAM is associated with poor clinical and pathological responses in breast cancer patients undergoing neoadjuvant chemotherapy

Neoadjuvant chemotherapy (NAC) is a standard regimen in treatment of breast cancer patients, but some are resistant to NAC. We hypothesized that breast cancer cells overexpressing epithelial cell adhesion molecule (EpCAM) could be resistant to NAC, contributing to a poor prognosis. Seventy patients with breast cancer were treated with NAC. Core needle biopsy (CNB) specimens and resected tumors before and after NAC, respectively, were examined for expression of EpCAM. In resected tumors, high EpCAM expression correlated with lymphovascular invasion status and nuclear grade (P = 0.01 and 0.008, respectively), and was associated with poor pathological and clinical responses (P < 0.001). High tumoral EpCAM expression in resected tumor was independently related to a poor pathological response. Patients with high EpCAM expression before and after NAC (high‐to‐high group) showed worse pathological and clinical responses (P = 0.008 and <0.001, respectively) than the patients with high and low EpCAM expression before and after NAC, respectively (high‐to‐low group). The overall survival rate of the high‐to‐high group appeared shorter compared with the high‐to low‐group (P = 0.049). Our findings imply that higher levels of EpCAM in breast cancer may be associated with poor response to NAC via a potential chemoresistant effect.