Fang Fang Liu

Breast carcinoma with micropapillary features: clinicopathologic study and long-term follow-up of 100 cases.

To study the clinicopathologic characteristics and prognosis of invasive micropapillary carcinoma of breast (IMPC), 100 cases of invasive breast carcinoma with an IMPC component were reviewed. Compared with invasive ductal carcinoma, not otherwise specified, with similar histologic grades, carcinomas with IMPC were larger sized, had a higher lymph node metastasis rate with more nodes involved per case, and exhibited increased lymphovascular invasion. The presence of IMPC strongly correlated with the more aggressive behavior. No significant association was established between the proportion of the IMPC component and overall tumor size, histologic grade, lymph node metastasis rate, and distant metastasis, but a trend was noted. Long-term follow-up demonstrated a poorer 5-year and 10-year survival rate for patients with breast carcinoma containing an IMPC component. Breast carcinomas with micropapillary features are more aggressive tumors with a poorer prognosis. This specific structure should be carefully evaluated in the surgical pathology examination of breast carcinoma specimens.

Tumor Secretion of CCL22 Activates Intratumoral Treg Infiltration and Is Independent Prognostic Predictor of Breast Cancer

It has been reported that dense intratumoral infiltration of Foxp3 +Tregs (Tregs) was an independent factor for poor prognosis of breast cancer (BC) patients. However, the cytokines activating the Treg infiltration are not known. This study was undertaken to evaluate the role of CCL22 and TGF-β1 in this cascade and their prognostic significance for BC patients. 417 cases of invasive breast cancer were selected from the prior study cohort and the expressions of CCL22 and TGF-β1 were assessed by immunohistochemistry. It was identified that tumor secretion of CCL22 was positively correlated with the intratumoral Treg infiltration (P<0.0001), but its association with lymphoid aggregates surrounding the tumor was not proven to be significant (P=0.056). Moreover, CCL22 expression was found to be associated with the tumor histological features known to be related with unfavorable prognosis of patients, including high histological grade (P<0.0001), negative ER (P<0.0001), negative PR (P=0.001), and HER2 amplification (P=0.028). Similar to intratumoral Treg infiltrates, CCL22 tumor secretion correlated with the prognosis of the molecular subtypes of breast carcinoma (P<0.0001). Univariate analysis revealed CCL22 to be an independent prognostic factor for overall survival (OS, P<0.0001) and progression-free survival (PFS, P<0.0001) of BC patients that were confirmed by multivariate analysis (P=0.011 and P=0.010 respectively). In contrast, although TGF-β1 expression was positively correlated with both Tregs infiltrates into the tumor bed and lymphoid aggregates surrounding the tumor (P=0.023; P=0.046, respectively), its expression was not significantly associated with the molecular subtypes of breast carcinoma and the prognosis of the patients. Our study indicates that both CCL22 and TGF-β1 are candidate chemoattractants for intratumoral Foxp3 +Tregs infiltration; however, unlike the later, CCL22 is an independent prognostic predictor of BC patients, and it therefore may have the potential to serve as a target for immunotherapeutic strategy of BC.

Overexpression of TNF‐α and TNFRII in invasive micropapillary carcinoma of the breast: clinicopathological correlations

Aims:u2002 Angiogenesis is essential for tumour growth and metastasis and tumour necrosis factor (TNF)‐α is a potent angiogenic factor. Invasive micropapillary carcinoma of the breast (IMPC), a rare subtype of breast cancer, possesses a lymphotropic nature with a high incidence of lymph node metastasis and poor prognosis. The aim was to evaluate the role of TNF‐α and its receptor TNFRII in the vascular development and metastasis of IMPC.

Syndecan binding protein (SDCBP) is overexpressed in estrogen receptor negative breast cancers, and is a potential promoter for tumor proliferation.

Background Syndecan binding protein (SDCBP), an adapter protein containing PDZ domains, contributes to the tumorigenicity and metastasis of many malignant tumors, such as malignant melanoma. Our study aimed in revealing the expression profile of SDCBP in breast cancer (BCa) and its role in tumor cell proliferation, and then exploring its value in the targeted treatment of BCa. Methodology/Principal Findings We first evaluated the SDCBP expression by immunohistochemistry in normal breast and BCa tissues. Then we explored the expression profile of SDCBP in different BCa cell lines. By constructing SDCBP-silenced BCa cell clones, we further assessed the effects of SDCBP suppression on tumor cells in vitro by cell culture and in vivo by tumorigenicity. SDCBP expression was detected in 80.6% (nu200a=u200a160) of BCa tissues, in contrast to its expression in 13% (nu200a=u200a23) of normal breast tissues (P<0.001). Among the tumors, the level of its expression was positively correlated with histological grade and tumor staging while negatively correlated with the estrogen receptor (ER) expression. Higher expression of SDCBP was also noted in ER-negative BCa cell lines. It was also identified that SDCBP expression was down-regulated in a dose-dependent mode by 17-β estradiol in estrogen-responsive MCF-7. Furthermore, SDCBP silence inhibited ER-negative tumor cell growth in vivo and in vitro. Cell cycle studies showed that SDCBP silence increased G1 cell population and resulted in related cell-cycle-regulator changes: up-regulation of p21 and p27 while down-regulation of cyclin E. Conclusion/Significance Our results suggested that SDCBP played an important role in tumor growth of ER-negative BCas. In these tumors where the estrogen signaling pathway is not available, SDCBP probably contribute to tumor growth through an alternative signaling pathway by promoting tumor cells passing the G1/S checkpoint into the cell cycle. Suppression of SDCBP expression may have its potential to become a targeted therapy for ER-negative BCas.

Overexpression of ubiquitous mitochondrial creatine kinase (uMtCK) accelerates tumor growth by inhibiting apoptosis of breast cancer cells and is associated with a poor prognosis in breast cancer patients

BACKGROUNDnUbiquitous mitochondrial creatine kinase (uMtCK), a mitochondrial isoenzyme of creatine kinase (CK), is a central controller of cellular energy homeostasis. Overexpression of uMtCK has been reported to be associated with a poor prognosis for several tumors. The aim of this study was to assess its association with breast cancer (BCa) and to further investigate its underlying mechanisms.nnnMETHODnWe first detected uMtCK expression by immunohistochemistry in human BCa tissues and assessed the association with the prognosis of patients. We then evaluated uMtCK expression in crowded and normal condition cultures of several human BCa cell lines. After two stable clones of the MDA-MB-231 cell line with high expression of uMtCK were established, cell growth, apoptosis and mitochondrial apoptotic pathway protein expression were measured in these clones. Finally, tumorigenicity of the above cells was assessed using nude mice to explore the relationship between uMtCK expression and tumor progression.nnnRESULTSnuMtCK expression was detected in 85.5% (47 of 55) of the invasive ductal carcinomas of breast tissue, not otherwise specified (IDC-NOS). Expression in BCa tissue was significantly associated with reduced progression-free survival (PFS; P=0.019) and overall survival (OS; P=0.022) of the patients. Up-regulation of uMtCK expression was identified in crowded BCa cells in culture, and the number of apoptotic cells was significantly decreased in uMtCK transfected MDA-MB-231 cell clones (P<0.01). Stabilization of the mitochondrial membrane potential (ΔΨm) and down regulation of cytochrome c (cyt c) and activated caspase 9, two components of mitochondrial apoptotic pathway proteins, were also identified in the same clones when cells were crowded in culture. In vivo studies revealed that the transfected tumor cells with uMtCK overexpression induced faster tumor growth in nude mice, along with accelerated animal body weight loss and a significantly lower tumor apoptotic index (AI) (P<0.001).nnnCONCLUSIONnThe results indicated that uMtCK expression is associated with a poor prognosis in BCa and might serve as a tumor marker. In vivo and In vitro evidence suggests that uMtCK overexpression promotes tumor growth by inhibiting apoptosis of tumor cells through stabilizing ΔΨm and down regulating mitochondrial apoptotic pathway proteins. Exploration of therapeutic agents targeting the expression of uMtCK may have practical value for BCa patients.

Accessory Breast Cancer Occurring Concurrently with Bilateral Primary Invasive Breast Carcinomas: A Report of Two Cases and Literature Review

The development of accessory breast tissue, which is found anywhere along the milk line, is attributed to the failure of milk line remnants to regress during embryogenesis. Primary tumors may arise from any ectopic breast tissue. Accessory breast cancer occurring concurrently with primary invasive breast cancer is extremely rare. Two such cases were reported in this article. One was a 43-year-old Chinese female who exhibited bilateral breast cancer (invasive ductal carcinoma, not otherwise specified, IDC-NOS) and an accessory breast carcinoma (IDC-NOS) incidentally identified in her left axilla. The ectopic breast tissue in her right axilla presented with adenosis. The patient was surgically treated, followed by postoperative docetaxel epirubicin (TE) chemotherapy. The second case was a 53-year-old Chinese female with bilateral breast cancer (apocrine carcinoma) accompanied by an accessory breast carcinoma (IDC-NOS) in her right axilla that was also incidentally identified. The patient was surgically treated after three doses of cyclophosphamide epirubicin docetaxel (CET) neoadjuvant chemotherapy, followed by adjuvant chemotherapy of the same regimen.

Dasatinib inhibits c-src phosphorylation and prevents the proliferation of Triple-Negative Breast Cancer (TNBC) cells which overexpress Syndecan-Binding Protein (SDCBP).

Triple negative breast cancer (TNBC) progresses rapidly but lacks effective targeted therapies. Our previous study showed that downregulating syndecan-binding protein (SDCBP) in TNBC inhibits the proliferation of TNBC cells. Dasatinib is a new small-molecule inhibitor of c-src phosphorylation. The aim of this study was to investigate if SDCBP is a potential marker to indicate whether a TNBC is suitable for dasatinib therapy. This study applied co-immunoprecipitation to identify the interaction between SDCBP and c-src in TNBC cell lines. In addition, immunohistochemistry was used to investigate SDCBP and tyrosine-419 phosphorylated c-src (p-c-src-Y419) expression in TNBC tissues. SDCBP-overexpressing MDA-MB-231 cells were then constructed to evaluate the effects of dasatinib on SDCBP-induced TNBC progression in vitro and tumor formation in nude mice. We found wild-type SDCBP interacted with c-src and promoted the phosphorylation of c-src; this phosphorylation was completely blocked by dasatinib. SDCBP lacking the PDZ domain had no such effect. Among the 52 consecutive random TNBC cases examined, the expression of SDCBP was consistent with that of p-c-src-Y419, and positively correlated with histological grading or Ki-67 levels. SDCBP overexpression significantly accelerated the proliferation and cell cycle progression of the TNBC cell line MDA-MB-231; these effects were prevented by dasatinib treatment. However, the subsequent inhibition of p27 expression partially restored the proliferation and viability of the TNBC cells. The results of this study suggest that SDCBP interacts with c-src, regulates G1/S in TNBC cells, and enhances tumor cell proliferation by promoting the tyrosine phosphorylation of c-src at residue 419. Dasatinib inhibits such phosphorylation and blocks SDCBP-induced cell cycle progression. Therefore, SDCBP might be an important marker for identifying TNBC cases that are suitable for dasatinib therapy.

Assessment of dual-probe Her-2 fluorescent in situ hybridization in breast cancer by the 2013 ASCO/CAP guidelines produces more equivocal results than that by the 2007 ASCO/CAP guidelines.

Dual-probe fluorescence in situ hybridization (D-FISH) is a widely accepted method to determine the gene amplification status of human epidermal growth factor receptor 2 (Her-2). In 2013, the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) updated the guidelines on the Her-2 testing for invasive breast cancer (BCa). The interpretation criteria for D-FISH changed accordingly. In this study, we compared the Her-2 FISH statuses based on the 2013 and 2007 ASCO/CAP guidelines in 1931 cases of BCa with Her-2 D-FISH testing at our hospital. We analyzed the clinicopathologic features of cases with equivocal results by the 2013 ASCO/CAP guidelines. Although the guideline update significantly improved the detection rate of Her-2 amplification, it also significantly increased the rate of equivocal results, posing a dilemma for clinical management. The equivocal results had a good reproducibility. The distribution of D-FISH-equivocal cases did not correlate with Her-2 status by immunohistochemistry, suggesting that Her-2 D-FISH equivocality may not reflect Her-2 overexpression. Compared with Her-2-negative cases by D-FISH, Her-2 D-FISH-equivocal cases had higher Ki67 expression, higher histological grade, more frequent lymph node metastasis, and lower estrogen receptor α expression, indicating a group of BCa with worse prognosis. The clinical significance of Her-2-equivocal results by D-FISH warrants further investigation.