Yi Zhao

US-guided Percutaneous Microwave Coagulation of Small Breast Cancers: A Clinical Study

PURPOSEnTo determine the feasibility of percutaneous microwave coagulation (PMC) for the treatment of small solitary breast cancers.nnnMATERIALS AND METHODSnWith approval of the institutional ethics committee and written informed consent, 41 patients with core-needle-biopsy-proved breast cancers 3.0 cm or less in diameter accessed by using ultrasonography (US) were recruited. US-guided PMC was performed with general anesthesia, followed immediately by mastectomy. Histochemical staining with α-nicotinamide adenine dinucleotide, reduced (NADH)-diaphorase was used to determine cell viability and the extent of PMC lesions.nnnRESULTSnThe mean tumor volume was 5.26 cm(3) ± 3.80 (standard deviation), with a range from 0.09 to 14.14 cm(3). PMC was successfully performed in all cases, with complete tumor ablation as assessed by using US. The mean time to reach complete ablation was 4.48 minutes, ranging from 3 to 10 minutes. With microscopic examination, 37 of 41 cases (90%; 95% confidence interval [CI]: 76.9%, 97.3%) showed complete tumor coagulation, as observed by using α-NADH-diaphorase staining. Of 38 cases diagnosed with invasive ductal carcinoma, 36 cases (95%; 95% CI: 82.3%, 99.4%) showed complete tumor coagulation. Slight thermal injuries to the skin and pectoralis major muscle, which proved reversible, were found in three cases.nnnCONCLUSIONnUS-guided PMC of small solitary breast cancers is feasible. Nevertheless, larger-scale clinical trials are still needed to validate PMC for adoption into a standard clinical practice.

STAT3 mediates resistance of CD44+CD24−/low breast cancer stem cells to tamoxifen in vitro

We sought to determine whether STAT3 mediated tamoxifen resistance of breast cancer stem cells in vitro. The capacities for mammosphere formation and STAT3 expression of CD44+CD24−/low MCF-7 and MCF-7 were observed. The CD44+CD24−/low subpopulation ratio and its sensitivity to adriamycin were analyzed in MCF-7 and TAM resistant (TAM-R) cells. Cell cycle, apoptosis, STAT3 and phospho-STAT3 changes were observed after treatment with tamoxifen. Small interference RNA-mediated knockdown of STAT3 in TAM-R cells was also performed. CD44+CD24−/low MCF-7 showed higher capacities for mammosphere formation and STAT3 expression than total MCF-7. The CD44+CD24−/low subpopulation was also upregulated in TAM-R cells with less sensitivity to adriamycin than MCF-7. Cell cycle changes, anti-apoptotic effects and STAT3 changes were also found. Meanwhile, the knock-down of STAT3 in TAM-R resulted in an increase in sensitivity to tamoxifen. It is concluded that STAT3 plays an essential role in breast cancer stem cells, which correlated with tamoxifen resistance.

Bloody nipple discharge is a predictor of breast cancer risk: a meta-analysis

Nipple discharge is a common complaint of patients with breast disease. The color of nipple discharge is always the first alarming symptom for patients. It is controversial whether the discharge color is an indicator of an underlying malignancy. The electronic database PubMed was searched for relevant articles. A meta-analysis about the association between the color of nipple discharge and breast cancer risk was conducted. Eight studies, including 3,110 patients, were eligible for this meta-analysis. Compared with patients in non-bloody nipple discharge group (179/1,478), patients in bloody nipple discharge group (404/1,632) had a markedly higher breast cancer risk (OR: 2.27, 95% CI: 1.32–3.89, Pxa0<xa00.001 for heterogeneity). Compared with patients in clear/serous group (71/575), patients in bloody nipple discharge group (326/1,271) also had a higher risk (OR: 2.49, 95% CI: 1.25–4.93, Pxa0=xa00.011 for heterogeneity). Furthermore, compared with patients in the colored group (55/448), patients in bloody nipple discharge group (296/1,124) (OR: 2.00, 95% CI: 0.74–5.45, Pxa0=xa00.009 for heterogeneity) had no significant difference. Besides, there was no significant difference between patients in colored group (55/448) and clear/serous group (61/470) (OR: 1.35, 95% CI: 0.83–2.18, Pxa0=xa00.707 for heterogeneity). Therefore, bloody nipple discharge could be a predictor of breast cancer risk among different colors of discharges. The symptom of bloody nipple discharge is helpful to the stratification of preoperative patients.

Tumor-derived VEGF-C, but not VEGF-D, promotes sentinel lymph node lymphangiogenesis prior to metastasis in breast cancer patients

Breast cancer usually initially metastases to the sentinel lymph nodes (SLNs). Recent studies have demonstrated that tumor cells induce SLN lymphangiogenesis before metastasis in several malignancies. In addition, tumor-derived VEGF-C or VEGF-D may induce lymphangiogenesis and promote lymph node metastasis. To explore the mechanisms of lymph node metastasis in breast cancer, we investigated whether primary tumors induce SLN lymphangiogenesis before metastasis and determined the function of tumor-derived VEGF-C and VEGF-D in SLN lymphangiogenesis. Expression of VEGF-C and VEGF-D was examined using immunohistochemistry in 63 primary breast tumors. No significant relationships between VEGF-C and VEGF-D (Pxa0=xa00.420), and VEGF-C or VEGF-D expression and clinical parameters (age, tumor size, grade, hormonal receptor status, her-2 status) were observed (Pxa0>xa00.05). Expression of the lymphatic-specific markers VEGFR-3, Prox-1 and LYVE-1 was measured using quantitative real-time RT-PCR in uninvolved SLNs from 63 patients and compared to control lymph nodes from patients with benign breast disease. Expression of Prox-1 and LYVE-1 mRNA was significantly higher in uninvolved SLNs from breast cancer patients than that in control lymph nodes (Pxa0<xa00.01). Interestingly, expression of VEGFR-3, Prox-1 and LYVE-1 was significantly higher in SLNs from patients with high VEGF-C-expressing tumors than low VEGF-C-expressing tumors (Pxa0<xa00.05), but not VEGF-D-high-expressing tumors (Pxa0>xa00.05). This study demonstrates that primary breast tumors induce SLN lymphangiogenesis before metastasis occurs and that tumor-derived VEGF-C, but not VEGF-D, plays an important role in SLN lymphangiogenesis in breast cancer.

A Novel Finding of Sentinel Lymphatic Channels in Early Stage Breast Cancer Patients: Which May Influence Detection Rate and False-Negative Rate of Sentinel Lymph Node Biopsy

Background The exact lymphatic drainage pattern of the breast hasnt been explained clearly. The aim of this study was to investigate the sentinel lymphatic channels (SLCs) in the cancerous breast. Whether the type of SLCs influenced the detection rate and false-negative rate of SLNB was also assessed. Methodology and Principal Findings Mimic SLNB was performed in 110 early-stage breast cancer patients with subareolar injection of blue methylene dye intraoperatively. Postoperatively, 110 specimens of modified radical mastectomy were examined for all blue SLCs after additional injection of methylene dye in peritumoral parenchyma. Interestingly, three types of SLCs, including superficial sentinel lymphatic channel (SSLC), deep sentinel lymphatic channel (DSLC), and penetrating sentinel lymphatic channel (PSLC) were found in 107 patients. Six lymphatic drainage patterns based on the three types of SLCs were observed in these 107 patients. The proportions of the drainage pattern SSLC, DSLC, PSLC, SSLC+DSLC, SSLC+PSLC, and DSLC+PSLC in the breast were 43%, 0.9%, 15.9%, 33.6%, 3.7% and 2.8%, respectively. The lymphatic drainage pattern in the breast was a significant risk factor for unsuccessful identification of sentinel lymph nodes (P <0.001) and false-negatives in SLNB (Pu200a=u200a0.034) with the subareolar injection technique. Conclusions Three kinds of SLCs are the basis of six lymphatic drainage patterns from the breast to the axilla. The type of SLCs is the factor influencing the detection rate and false-negative rate of SLNB. These findings suggest the optimal injection technique of the combination of superficial and deep injection in SLNB procedures. Future clinical studies are needed to confirm our novel findings.

A novel mouse model of gastric cancer with human gastric microenvironment.

Mouse models play an irreplaceable role in the in vivo research of human gastric cancer. In this study, we developed a novel human Gastric tissue-derived Orthotopic and Metastatic (GOM) mouse model of human gastric cancer, in which the human normal gastric tissues were implanted subcutaneously into immunodeficient mice to create a human gastric microenvironment. Then, human gastric cancer cells were injected into the implants. GOM model could mimic the interactions between human gastric microenvironment and human gastric cancer cells, which help exhibit the real characteristics of tumor cells, and finally mimic the clinical-like tumor proliferation and metastases of human beings.

Evaluation of the Role of Dynamic Contrast-Enhanced MR Imaging for Patients with BI-RADS 3–4 Microcalcifications

Objective The purpose of study was to prospectively evaluate the diagnostic performance of dynamic contrast-enhanced MR imaging in the differentiation of malignant lesions from benign ones in patients with BI-RADS 3–4 microcalcifications detected by mammography. Materials and Methods 93 women with 100 microcalcifications had undergone breast MRI from June 2010 to July 2013. Subsequently, 91 received open biopsy and 2 received stereotactic vacuum-assisted biopsy. All results were compared with histological findings. The PPV, NPV and area under curve (AUC) of the mammography and breast MRI were calculated. Results There were 31 (31.0%) BI-RADS 3 microcalcifications and 69 (69.0%) BI-RADS 4. The PPV and NPV of mammography is 65.2% (45/69) and 90.3% (28/31). The PPV and NPV of breast MRI was 90.2% (46/51) and 95.9% (47/49). Among 31 BI-RADS 3 microcalcifications, the PPV and NPV of breast MRI was 100% (3/3) and 100% (28/28). Among 69 BI-RADS 4 microcalcifications, the PPV and NPV of breast MRI was 89.6% (43/48) and 90.5% (19/21). The AUC of mammography and breast MRI assessment were 0.738 (95% CI, 0.639–0.837) and 0.931 (95% CI, 0.874–0.988) (p<0.05). Conclusion Dynamic contrast-enhanced MR imaging of breast is able to be applied to predict the risk of malignance before follow-up for BI-RADS 3 microcalcifications and biopsy for BI-RADS 4 microcalcifications.

Cancer/testis antigen SSX2 enhances invasiveness in MCF-7 cells by repressing ERα signaling.

Cancer/testis antigen (CTA) SSX2, which is silent in most normal adult tissues and expressed in various malignant tumors, has been identified for decades. Expression of SSX in tumors has been associated with advanced stages and worse patient prognosis. However, little is known about its role in breast cancer. The SSX2 expression plasmid constructed was stably transfected into the breast cancer cell line MCF-7. The influence of SSX2 on MCF-7 cells was assessed using MTT assay, flow cytometry, transwell invasion assay and in vivo tumorigenicity assay. A comparative proteomic approach was performed to identify and clarify the underlying molecular mechanisms. SSX2 expression was more pronounced in ERα-negative breast cancer cells compared with the positive ones. Overexpression of SSX2 induced cell growth and prompted cell invasion. Both ERα and E-cadherin expression were suppressed in the SSX2 overexpressing MCF-7 cells. Eleven known proteins were identified with significant differential expression. Among these, five were decreased, while other six were increased in the SSX2 overexpressing MCF-7 cells. These results suggested SSX2 may enhance invasiveness in MCF-7 cells both in vivo and in vitro. The regulation of ERα signaling by target proteins of SSX2 may explain the metastatic potential of breast cancer cells.

Reactivation of Syk gene by AZA suppresses metastasis but not proliferation of breast cancer cells

Spleen tyrosine kinase (Syk) is reported to be involved in the suppression of proliferation and invasion of breast cancer. Methylation-mediated Syk gene silencing is found in a subset of breast cancer. In this study, we used a DNA methyltransferase inhibitor, 5-aza-2-deoxycytidine (AZA), to restore Syk expression of breast cancer cells. Surprisingly, we found that AZA treatment could reestablish the expression of Syk, but not affect the proliferation of breast cancer cells. Moreover, tumor formation in situ by MDA-MB-435s treated with (+) or without (−) AZA in a nude mice MFP (Mammary fat pad) model did not show significant difference, too. Interestingly, pulmonary metastasis was still significantly suppressed in MDA-MB-435s(+) group (1/9 vs. 7/9). Our findings suggested Syk may be more correlated to metastasis rather than proliferation. This study implied a potential use of Syk methylation as a valuable biomarker to detect high metastatic potential cancerous lesions and the prospect of AZA to join the arsenal of drug candidates to be developed as a new reagent for management of advanced breast cancer.

Screening and analysis of breast cancer genes regulated by the human mammary microenvironment in a humanized mouse model

Tumor microenvironments play critical regulatory roles in tumor growth. Although mouse cancer models have contributed to the understanding of human tumor biology, the effectiveness of mouse cancer models is limited by the inability of the models to accurately present humanized tumor microenvironments. Previously, a humanized breast cancer model in severe combined immunodeficiency mice was established, in which human breast cancer tissue was implanted subcutaneously, followed by injection of human breast cancer cells. It was demonstrated that breast cancer cells showed improved growth in the human mammary microenvironment compared with a conventional subcutaneous mouse model. In the present study, the novel mouse model and microarray technology was used to analyze changes in the expression of genes in breast cancer cells that are regulated by the human mammary microenvironment. Humanized breast and conventional subcutaneous mouse models were established, and orthotopic tumor cells were obtained from orthotopic tumor masses by primary culture. An expression microarray using Illumina HumanHT-12 v4 Expression BeadChip and database analyses were performed to investigate changes in gene expression between tumors from each microenvironment. A total of 94 genes were differentially expressed between the primary cells cultured from the humanized and conventional mouse models. Significant upregulation of genes that promote cell proliferation and metastasis or inhibit apoptosis, such as SH3-domain binding protein 5 (BTK-associated), sodium/chloride cotransporter 3 and periostin, osteoblast specific factor, and genes that promote angiogenesis, such as KIAA1618, was also noted. Other genes that restrain cell proliferation and accelerate cell apoptosis, including tripartite motif containing TRIM36 and NES1, were downregulated. The present results revealed differences in various aspects of tumor growth and metabolism between the two model groups and indicated the functional changes specific to the human mammary microenvironment.