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Objective: To investigate the interaction of body mass index(BMI)and a single nucleotide polymorphism (SNP, rs17883901) in catalytic subunit of glutamate-cysteine ligase (GCLC) on breast cancer risk., Methods: A total of 839 women with incident breast cancer and 863 age-matched controls without cancer were recruited at the same period in three affiliated hospitals of Sun Yat-sen University in Guangzhou from October 2008 to June 2010. GCLC rs17883901 was genotyped by MALDI-TOF-MS. Binary unconditional logistic regression was applied to calculate odds ratios and 95% confidence intervals., Results: The difference of present BMI and BMI at age 20 was not statistically significant between cases and controls, either as the genotypes of GCLC. No association was found between BMI at present and premenopausal or postmenopausal breast cancer risk. But we found that women who had a BMI at age 20 of 18.5 to 22.9 had a marginally decreased risk of premenopausal breast cancer [OR and 95%CI:0.69(0.48, 1.00)]. Among women with CT/TT genotypes, whose present BMI was greater than 25 had a increased risk [OR and 95%CI:1.91(1.09, 3.36)] of breast cancer and a decreased risk [OR and 95%CI:0.56 (0.31,0.99)] with a BMI at age 20 of 18.5 to 22.9. There was a interaction between GCLC gene(rs17883901)and BMI at present in breast cancer risk (P = 0.043), which was not found between rs17883901 and BMI at age 20., Conclusion: Our findings indicate BMI at age 20 may be a protective factor of premenopausal breast cancer, while no association appears between GCLC(rs17883901) and breast cancer. Obesity at present may significantly increase the risk of breast cancer among women with CT/TT genotypes of GCLC (rs17883901).

Objective: The aim of this study was to investigate the association between urinary cadmium and clinicopathological characteristics of breast cancer., Methods: The clinicopathological characteristics of 240 patients with breast cancer were obtained and urine specimens were collected from October 2009 to July 2010. The concentration of urinary cadmium was determined by inductively coupled plasma mass spectrometry (ICP-MS). χ(2) test and Wilcoxon rank sum test were used to analyze whether urinary cadmium is associated with clinicopathological characteristics of breast cancer., Results: The median concentration of urine cadmium of 240 patients was 1.99 µg/g (25th percentile, 1.32 µg/g; 75th percentile, 2.88 µg/g). HER-2 positive rate, regional/distant metastasis rate, and advanced stage rate in patients with the highest tertile of cadmium concentration were significantly higher than those in the patients with second and lowest Cd tertiles (P = 0.042, P = 0.028 and P = 0.017, respectively), and 28.2% vs. 16.5% for HER-2 and 47.2% vs. 32.0% for regional/distant metastasis, respectively. There were still significant associations between urinary cadmium levels and these clinicopathological parameters after being adjusted in age by unconditional logistic regression model, respectively (P < 0.05)., Conclusions: The results of this study suggest that urinary cadmium levels are associated with the HER-2 status, regional/distant metastasis status and stages of breast cancer, respectively. Cadmium may induce highly aggressive breast cancer in humans.

A major obstacle to developing small interfering RNAs (siRNAs) as cancer drugs is their intracellular delivery to disseminated cancer cells. Fusion proteins of single-chain fragmented antibodies (ScFvs) and positively charged peptides deliver siRNAs into specific target cells. However, the therapeutic potential of ScFv-mediated siRNA delivery has not been evaluated in cancer. Here, we tested whether Polo-like kinase 1 (PLK1) siRNAs complexed with a Her2-ScFv-protamine peptide fusion protein (F5-P) could suppress Her2(+) breast cancer cell lines and primary human cancers in orthotopic breast cancer models. PLK1-siRNAs transferred by F5-P inhibited target gene expression, reduced proliferation, and induced apoptosis of Her2(+) breast cancer cell lines and primary human cancer cells in vitro without triggering an interferon response. Intravenously injected F5-P/PLK1-siRNA complexes concentrated in orthotopic Her2(+) breast cancer xenografts and persisted for at least 72 hours, leading to suppressed PLK1 gene expression and tumor cell apoptosis. The intravenously injected siRNA complexes retarded Her2(+) breast tumor growth, reduced metastasis, and prolonged survival without evident toxicity. F5-P-mediated delivery of a cocktail of PLK1, CCND1, and AKT siRNAs was more effective than an equivalent dose of PLK1-siRNAs alone. These data suggest that F5-P could be used to deliver siRNAs to treat Her2(+) breast cancer.

Objective: To evaluate the clinical value of GeneSearch(TM) BLN Assay as an intra-operative diagnostic method of sentinel lymph node (SLN) for breast cancer patients., Methods: A total of 479 consecutive patients from six centers were involved in this prospective study. The SLNs were identified, dissected and then sectioned along the short axis into multiple blocks. The odd blocks were tested intra-operatively by the above-mentioned assay and the even blocks assessed post-operatively by histopathologic examination. The 4 - 6 µm thick stepwise sectioning permanent HE slides were prepared every 150 µm and one block yielded 6 slides. In addition, the even blocks of 136 patients were prepared for frozen section (FS) and all blocks of 156 patients evaluated intra-operatively by touch imprint cytology (TIC)., Results: In the node basis analysis, its accuracy, sensitivity, specificity, positive predict value (PPV) and negative predict value (NPV) were 93.0%, 85.6%, 94.6%, 76.6% and 96.9% respectively. Its sensitivity was similar to that of FS (84.9%, P = 0.885) and significantly higher than that of TIC (70.0%, P = 0.007). When assessing nodes with macro-metastases, its sensitivity was similar to that of FS (93.6% vs 95.6%, P = 0.558) and significantly higher than that of TIC (93.6% vs 80.9%, P = 0.011). When assessing nodes with micro-metastases, it had a higher sensitivity than that of FS (57.5% vs 44.4%, P = 0.356) and TIC (57.5% vs 30.8%, P = 0.094). In the patient basis analysis, the accuracy, sensitivity, specificity, PPV and NPV were 91.4%, 87.5%, 92.9%, 81.8% and 95.3% respectively. Its sensitivity was similar to that of FS (84.5%, P = 0.576) and significantly higher than that of TIC (75.0%, P = 0.049). After adjustment, it had the accuracy, sensitivity, specificity, PPV and NPV of 91.7%, 83.5%, 95.2%, 88.3% and 93.0% respectively. Its sensitivity was higher than that of FS (72.1%, P = 0.054) and significantly higher than that of TIC (66.7%, P = 0.011). The two had no significant difference in the sensitivity and specificity. After a learning curve of around 10 cases, it could be performed in a median time of around 35 min. The threshold cycle time values of MG and CK-19 were 36 and 31 respectively. The type of metastases could be estimated approximately according to the cycle time values. The cycle time values of MG under 33 indicated SLN macro-metastases and those of 33-36 denoted micro-metastases. The values of CK-19 under 29 indicated SLN macro-metastases and those of 29-31 denoted micro-metastases., Conclusion: As an accurate and rapid intra-operative assay for breast sentinel lymph nodes, the GeneSearch(TM) BLN Assay may replace FS and TIC in general medical practice.

Objective: To study the BRCA1 mutations in patients with early-onset breast cancer and their affected relatives in Guangdong province and explore the relationship between BRCA1 mutation and the expressions of estrogen receptor(ER), progesterone receptor(PR), HER2 and ALN., Methods: From 58 patients with early-onset breast cancer and their affected relatives, the genomic DNA was extracted from the peripheral blood mononuclear cells and the coding regions of the BRCA1 gene was amplified using polymerase chain reaction. BRCA1 gene mutations were screened by denaturing high performance liquid chromatography (DHPLC) and subsequent direct DNA sequencing. The expression of ER, PR, HER2 and ALN were detected with immunohistochemistry and their relations with the gene mutation were analyzed., Results: Disease-related BRCA1 mutations were detected in 2 of the 58 patients, who were younger than 35 years old, including 1 with a novel splice-site mutation (IVS5-1 G-->A). No association was found between this novel mutation and the expressions of ER, PR, HER2 and ALN., Conclusion: The incidence of BRCA1 mutation is significantly lower in patients with early-onset breast cancer and their affected relatives in Guangdong province than in the Western populations. The novel mutation identified in BRCA1 gene may represent a mutation characteristic of the patients in Guangdong province. BRCA1 gene mutations may not have any relation with the expression of ER, PR, HER2 and ALN.

Objective: To evaluate the efficacy and safety of combination of docetaxel plus epirubicin (TE) versus docetaxel plus cisplatin (TP) as first-line chemotherapy for locally advanced or metastatic breast cancer., Methods: Eighty-eight patients were randomized into two groups with a ratio of 2:1, either to receive TE or TP regimen. The patients received docetaxel 75 mg/m2 plus epirubicin 60 mg/m2 (TE group) or docetaxel 75 mg/m2 plus cisplatin 75 mg/m2 (TP group) administrated intravenously. Both regimens were once repeated 3 weeks later. The efficacy, time to progression and safety were evaluated at the end of the second cycle., Results: Complete response was achieved in 5% of TE group and 3.6% of TP. Overall (complete plus partial) response rates in TE and TP group were 48.3% and 60.7%, respectively (P = 0.2788). Disease control rates (CR + PR + SD) for TE and TP groups were 83.6% and 80%, respectively (P = 0.4899). The median time to progression (TTP) was 10 months for TE versus 8 months for TP groups (P = 0.7119). The major grade III or IV toxicities were neutropenia (66.7% in TE; 53.6% in TP, P = 0.2373); and alopecia (30.0% in TE; 10.7% in TP, P = 0.0508)., Conclusion: Both TE and TP regimens as first-line chemotherapy were similarly effective, safe and tolerable in the treatment for locally advanced or metastatic breast cancer.

Objective: To study the effect of alternatively activated macrophages /mononuclear phagocytes(MNP) on breast cancer cells and explore the mechanisms for the action of tumor-associated macrophages in breast cancer., Methods: Human peripheral blood monocytes were isolated and cultured in vitro and divided into 3 groups, namely classically activated monocytes (CAM) which were induced by lipopolysaccharide, alternatively activated monocytes (AAM) induce by IL-4, and control cells treated with the culture medium only. After cell culture for 48-72 h, the mRNA of tumor necrosis factor-alpha (TNF-alpha), alternative monocytes activation- associated CC-chemokine 1 (AMAC-1), and beta-actin of the 3 groups were extracted for RT-PCR, or the cells were cocultured with breast cancer cell line SKBR3, or seeded in chicken chorioallantoic membrane along with SKBR3., Results: TNF-alpha mRNA was significantly increased in CAM, and AMAC-1 was highly expressed in AAM. The coculture experiments showed that CAM exhibited obvious inhibitory effect on SKBR3 cells after a 3-day culture whereas AAM significantly promoted the growth of SKBR3 cells after a 5-day culture. In chicken on chorioallantoic membrane experiment, the macrophages promoted tumor angiogenesis and AAM showed the most obvious effect., Conclusion: IL-4 induces high expression of AMAC-1, a molecular marker of AAM, in the macrophages, and AAM can promote the growth of SKBR3 cells and tumor angiogenesis.

Objective: To study the feasibility of vector-mediated RNA interference for HER-2-positive breast cancer therapy., Methods: A plasmid vector capable of mediating HER-2 RNA interference was constructed, and HER-2-positive breast cancer cell line SKBR-3 was transfected with this constructed vector. The expression of HER-2 mRNA and protein was analyzed by RT-PCR and Western blotting, and the growth and apoptosis of SKBR-3 cells was analyzed after transfection., Results: The expressions of HER-2 mRNA and HER-2 protein was downregulated in response to vector-mediated HER-2 RNA interference, which also resulted in tumor cell growth inhibition and increased number apoptotic cells., Conclusion: HER-2 is a good target for RNA interference and RNA interference targeting HER-2 can lead to HER-2 breast cancer cell apoptosis and growth inhibition.

Objective: To investigate the clinical response, pathological complete response (pCR), tumor resection rate and safety of neoadjuvant chemotherapy with docetaxel and epirubicin (ET) for locally advanced breast cancer (LABC)., Methods: From March to December 2001, 40 women with LABC, aged from 28-67 (medium 48) years were alloted. Twenty patients had clinical stage IIIa disease, 15 had stage IIIb disease and 5 stage IV patients who had ipsilateral sura-clavicular metastasis. The dose was: epirubicin (E) 60 mg/m2, docetaxel (T) 75 mg/m2 every 3 weeks, with G-CSF given preventively. After 2 cycles of ET, a pilot clinical response evaluation was performed by investigators for each patient to decide if she should receive another 1-2 cycles of ET before surgery or radiation therapy., Results: Thirty-eight patients received 2-3 cycles of ET regimen. The pCR, clinical complete response (cCR) and clinical partial response (cPR) rates were 15.0%, 20.0% and 52.5%, respectively. Tumor resection rate in this group was 92.5%. Incidence of III/IV Grade neutropenia was 8.4%/14.0% of cycles, and 3 patients suffered from neutropenia with fever. Non-hematological adverse events were alopecia, nausea, vomiting, fluid retention, myalgia, arthralgia and nail disorders, which were mild to moderate., Conclusion: Neo-adjuvant chemotherapy with a combination of docetaxel and epirubicin is effective and well tolerated by women with locally advanced breast cancer.