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In this study high‐valent Cu(III) trifluoromethyl compounds in combination with DMSO is shown to be an efficient and mild oxidizing system for the conversion of alcohols to ketones (aldehydes as well). Trifluoromethoxylated sulfonium species is proposed to be initially formed that engages in crucial steps of alkoxy replacement at sulfonium center and deprotonative collapse of the resulting alkoxysulfonium intermediate in the presence of a base. This reaction is highly selective without over‐oxidation, and can tolerate a broad range of functional groups owing to mild oxidizing ability of the Cu(III)‐CF3/DMSO system and the inert N2 conditions. This method can be applied to the synthesis and functionalization of commercial drug compounds. This study illustrates an unusual reactivity property of high‐valent Cu(III) trifluoromethyl compounds beyond the conventional CF3 group transfer reactivity, and opens up new opportunities for developing novel reactions of Cu(III)‐CF3 compounds. The combined use of high‐valent Cu(III)‐CF3 compound and DMSO is anticipated to find more applications to develop other novel and useful oxidation reactions. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the feasibility of using a multigene signature to tailor individualised adjuvant therapy for patients with operable triple negative breast cancer., Design: Randomised, multicentre, open label, phase 3 trial., Setting: 7 cancer centres in China between 3 January 2016 and 17 July 2023., Participants: Female patients aged 18-70 years with early triple negative breast cancer after definitive surgery., Interventions: After risk stratification using the integrated signature, patients at high risk were randomised (1:1) to receive an intensive adjuvant treatment comprising four cycles of docetaxel, epirubicin, and cyclophosphamide followed by four cycles of gemcitabine and cisplatin (arm A; n=166) or a standard treatment of four cycles of epirubicin and cyclophosphamide followed by four cycles of docetaxel (arm B; n=170). Patients at low risk received the same adjuvant chemotherapy as arm B (arm C; n=168)., Main Outcome Measures: The primary endpoint was disease-free survival in the intention-to-treat analysis for arm A versus arm B. Secondary endpoints included disease-free survival for arm C versus arm B, recurrence-free survival, overall survival, and safety., Results: Among the 504 enrolled patients, 498 received study treatment. At a median follow-up of 45.1 months, the three year disease-free survival rate was 90.9% for patients in arm A and 80.6% for patients in arm B (hazard ratio 0.51, 95% confidence interval (CI) 0.28 to 0.95; P=0.03). The three year recurrence-free survival rate was 92.6% in arm A and 83.2% in arm B (hazard ratio 0.50, 95% CI 0.25 to 0.98; P=0.04). The three year overall survival rate was 98.2% in arm A and 91.3% in arm B (hazard ratio 0.58, 95% CI 0.22 to 1.54; P=0.27). The rates of disease-free survival (three year disease-free survival 90.1% v 80.6%; hazard ratio 0.57, 95% CI 0.33 to 0.98; P=0.04), recurrence-free survival (three year recurrence-free survival 94.5% v 83.2%; 0.42, 0.22 to 0.81; P=0.007), and overall survival (three year overall survival 100% v 91.3%; 0.14, 0.03 to 0.61; P=0.002) were significantly higher in patients in arm C than in those in arm B with the same chemotherapy regimen. The incidence of grade 3-4 treatment related adverse events were 64% (105/163), 51% (86/169), and 54% (90/166) for arms A, B, and C, respectively. No treatment related deaths occurred., Conclusions: The multigene signature showed potential for tailoring adjuvant chemotherapy for patients with operable triple negative breast cancer. Intensive regimens incorporating gemcitabine and cisplatin into anthracycline/taxane based therapy significantly improved disease-free survival with manageable toxicity., Trial Registration: ClinicalTrials.gov NCT02641847., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from the National Key Research and Development Project of China, National Natural Science Foundation of China, Science and Technology Commission of Shanghai Municipality, Shanghai Key Laboratory of Breast Cancer, SHDC Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals, and CSPC Pharmaceutical Co Ltd, Shijiazhuang, China, for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To examine the effect of postoperative pregnancy upon the prognosis of young Chinese breast cancer patients., Methods: Four hundred and thirty-two female unilateral breast cancer patients aged 35 or younger were retrospectively reviewed. Kaplan-Meier analysis and Log Rank test were used for univariate analysis of factors predictive of disease-free survival (DFS) and overall survival (OS). Multivariate analysis was carried out using the Cox proportional hazards model., Results: Eighteen patients were identified to have postoperative pregnancy, including 5 full-term pregnancy and 13 abortions with the earliest pregnancy taking place at Month 17 post-operation. After a median follow-up of 62 months (6 - 237 months), the DFS and OS rates were 72.5% (313/432) and 88.7% (383/432) respectively. On multivariate analysis, postoperative pregnancy, clinical stage and number of pathologically involved axillary lymph node were significantly associated with DFS. And the axillary lymph node status was also predictive of OS. No death occurred in patient with postoperative pregnancy. There was no significant association between postoperative pregnancy and OS., Conclusion: Postoperative pregnancy has no adverse effect upon the prognosis of young breast cancer patients.

Objective: To identify predictive markers of the long-term outcome for neo-adjuvant chemotherapy (NC) in locally advanced breast cancer (LABC) treated with intravenous vinorelbine (V) and epirubicin (E) combination regimen., Methods: One hundred and nineteen patients with LABC were treated from September 2001 to May 2006. All patients were diagnosed as invasive breast cancer by 14G core needle biopsy and treated with three cycles of VE regimen before the operation. The patients were subjected to surgery and subsequently were given other three cycles of VE or cyclophosphamide+epirubicin+fluorouracil (CEF) regimen according to the clinical responses. Local-regional radiotherapy was applied to all patients after the chemotherapy and followed by hormone-therapy according to hormone receptor status. The impact of clinical, pathological, and immunohistochemical features on disease free survival (DFS) and overall survival (OS) was evaluated., Results: All patients were evaluable for responses: clinical complete response was documented in 27 patients (22.7%), 78 patients (65.5%) obtained partial clinical response. The pathological complete response was found in 22 cases (18.5%). Of the patients, 115 cases (96.6%) were followed-up for a median time of 63.4 months (range, 9-76 months), the 5-year DFS rate and OS rate was 58.7% and 71.3%, respectively. On multivariate analysis, high pre-Ki-67 (P=0.012) and post-Ki-67 expression (P=0.045), no pathological complete response after NC (P=0.034) were associated with the higher risk of disease relapse; high pre-Ki-67 (P=0.017) and post-Ki-67 expression (P=0.001), negative pre-ER (P=0.002) and no pathological complete response after NC (P=0.034) were associated with a shorter survival., Conclusion: Pathological response in primary tumor, pre-Ki-67 and post-Ki-67 expression, pre-ER expression are important predictors of long-term outcome for LABC patients with three cycles of VE regimen before operation.

BRCA2 is closely related to the pathogenesis of breast cancer. In the present study, we found that estrogen can activate BRCA2 transcription, which is estrogen receptor (ER) alpha-dependent. During estrogen treatment, ERalpha interacted with CREB-binding protein/p300, p68/p72, and MyoD and formed an activating transcriptional complex that could bind to many Sp1 sites on the BRCA2 promoter and activate its transcription by inducing histone acetylations. MyoD is a new component of ERalpha complex. ERbeta or p53 attenuated ERalpha-mediated transcriptional activation by preventing the recruitment of ERalpha transcriptional complex and histone acetylations on the BRCA2 promoter. ERbeta interacted with ERalpha and CREB-binding protein/p300 and formed a weak activating transcriptional complex that competed for binding to Sp1 sites with ERalpha transcriptional complex and slightly attenuated BRCA2 transcription. Different from ERbeta, p53 interacted with HDAC1 and CtBP1 and formed an inhibiting transcriptional complex that could compete for binding to Sp1 sites with ERalpha transcriptional complex and inhibit BRCA2 transcription more significantly.

Objective: To investigate the relationship between LKB1 gene and invasion of breast cancer cells., Methods: Human breast cancer cells of the line MDA-MB-435 were cultured and transfected with plasmids with or without LKB1 gene. The clone of the transfected MDA-MB-435 cells with high expression of LKB1 was called MDA-MB-435/LKB1 (H), and that with low expression of LKB1 was called MDA-MB-435/LKB1 (L). The MDA-MB-435 cells transfected with blank vector was called MDA-MB-435/vec. MDA-MB-435 cells without transfection were used as controls. RT-PCR was used to detect the mRNA expression of the invasion-related factors of breast cancer: matrix metalloproteinase (MMP)-2, MMP-9, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF), and Western blotting was used to detect the protein expression of these factors. Gelatin zymography was used to expression of the secretive MMP-2 and MMP-9. Transwell test was used to examine the membrane penetration of the different MDA-MB-435 cells., Results: The invasion rate was (47.6 +/- 1.3)% in the MDA-MB-435 cells, (45.6 +/- 1.2)% in the MDA-MB-435/vec cells, both significantly higher than those of the MDA-MB-435/LKB1 (H) and MDA-MB-435/LKB1 (L) cells [(18.1 +/- 1.0)% and (22.4 +/- 1.8)% respectively, all P < 0.01], with significant difference between the latter 2 groups (P < 0.05). The mRNA expression and protein expression of MMP-2, MMP-9, VEGF, and b-FGF were all significantly lower in the MDA-MB-435/LKB1 cells. Gelatin zymography showed that the secretive MMP-2 and MMP-9 were expressed at the protein level significantly lower in the MDA-MB-435/LKB1 cells., Conclusion: LKB1 gene inhibits the invasion of breast cancer cells.

Objective: To investigate the expression of ER alpha in chemically induced, ER alpha-negative human breast cancer MDA-MB-435 cells and its restoration of the responsiveness to endocrine therapy., Methods: MDA-MB-435 cells were treated with HDAC inhibitor trichostatin A(TSA)and DNMT1 inhibitor 5-AZA-CdR (AZA). The mRNA level of ER alpha, PR and PS2 in treated MDA-MB-435 cells was detected by RT-PCR. The WST-8 (water-soluble tetrazolium salt-8) method was used to analyze the proliferation rate of the cells. Xenograft in female nude mice was used to further explore the change of proliferation rate of treated MDA-MB-435 cells in vivo., Results: After treatment with AZA and TSA, mRNA expression of ER alpha, PR and pS2 was up-regulated in MDA-MB-435 cells. The mRNA level of ER alpha was the hightest when MDA-MB-435 cells were treated with 2.5 micromol/L AZA and 100 ng/ml TSA. The treated MDA-MB-435 cells showed different proliferation rate in various media containing different concentration of estrodial. The MDA-MB-435 cells showed down-regulated proliferation rate after treatment with the combination of 2.5 micromol/L AZA and 100 ng/ml TSA, and 4-OH tamoxifen could suppress the growth rate of the induced MD-MBA-435 cells but not the untreated cells. The treated MDA-MB-435 cells showed slower proliferation rate than that of untreated cells in vivo (P <0. 01), and the proliferation rate of the treated MDA-MB-435 cells became lower when the nude mice were deprived of estrogen by castration (P <0. 01)., Conclusion: After treatment with TSA and AZA, ER alpha-negative MDA-MB-435 cells can express functional ER alpha and regain responsiveness to estrogen both in vitro and in vivo. HDAC inhibitor and DNMT1 inhibitor may play an important role in restoration of sensitivity of ER alpha-negative breast cancers to endocrine therapy.

Objective: To analyze the relationship between Duffy antigen receptor for chemokines (DARC) and the metastasis potential in human breast cancer. METHODS Breast cancer tissue sections from 75 patients, grouped according to the local lymph node status were examined immunohistochemically for protein level of DARC. Microvessel density (MVD) was counted by endothelial cells immunostained using anti-CD34 antibody., Results: Strong positive DARC immunostaining in lymph node negative and positive groups was detected in 31 cases (81.6%) and 18 cases (48.6%), respectively (P < 0.01). MVD was (35.67 +/- 17.96)/HP and (53.38 +/- 20.29)/HP in DARC strong positive and less positive cases (P < 0.01). In those patients with lung, bone, hepatic distant metastasis (13 cases), 9 cases (69.2%) were DARC less positive, 4 cases (30.8%) were DARC strong positive. The correlation coefficient was -0.412 between DARC expression and MVD and the corresponding value was -0.346 between DARC expression and lymph node status and -0.333 between DARC expression and distant metastasis in breast cancer., Conclusion: DARC may play a negative role in the process of neoangiogenesis, and probably has an association with the lymph node status.

To better understand the molecular mechanisms underlying breast cancer metastasis and search for potential markers for metastatic progression, we have developed a highly metastatic variant of human MDA-MB-435 breast cancer cell line through in vivo stepwise selection of pulmonary metastatic cells caused by parental MDA-MB-435 cells in the athymic mice. Comparative proteomic analysis using 2-DE and LC-IT-MS revealed that 102 protein spots were reproducibly altered more than three-fold between the selected variant and its parental counterpart. Eleven differentially expressed protein spots were identified with high confidence using SEQUEST with uninterpreted tandem mass raw data. Cathepsin D precursor, peroxiredoxin 6 (PDX6), heat shock protein 27 (HSP27), HSP60, tropomyosin 1 (TPM1), TPM2, TPM3, TPM4, 14-3-3 protein epsilon, and tumor protein D54 were up-regulated in the highly metastatic variant, whereas alpha B-crystalline (CRAB) was only detected in its parental counterpart. Differential expression was confirmed for four proteins including PDX6, CRAB, TPM4, and HSP60 by real-time quantitative PCR and Western blotting analysis in our model. Immunohistochemical analysis in 80 breast cancer donors demonstrated a significant association of TPM4 (p = 0.002), HSP60 (p = 0.001), PDX6 (p = 0.002) but not CRAB (p = 0.113) staining with the presence of lymph node metastasis. In addition, TPM4 staining was also associated with clinical stage (p = 0.000), but no significant association was found between TPM4, PDX6, CRAB, and HSP60 expression and tumor size, hormone receptor, and HER-2 status (p > 0.05). The functional implication of these identified proteins was also discussed. These proteomic data are valuable and informative for understanding breast cancer metastasis and searching for potential markers for metastatic progression.

Objective: To study the effects of Duffy antigen receptor for chemokines (DARC) on the tumorigenesis and metastasis of breast cancer., Methods: Human breast cancer cells of the line MDA-MB-435HM with a great potentiality of metastasis were cultured and then divided into 3 groups: MDA-MB-435HM-DARC cell group, to be transfected with pcDNA3/DARC FyB containing human DARC cDNA; MDA-MB-435HM-vect cell group, to be transfected with blank plasmid pcDNA3; and MDA-MB-435HM cell group without transfection. Female BALB/c nude mice were implanted with MDA-MB-435HM cells into the nipple. The size of the implanted cancer was measured once a week. The mice were killed 4, 6, and 8 weeks after the implantation respectively and their lungs were taken out to observe the number of metastatic tumor. Immunohistochemical staining was performed to calculate the microvascular density (MVD). Western blotting was used to detect the matrix metalloproteinase (MMP)-9 protein expression of the lung tissues. ELISA was used to detect the concentrations of the 2 DARC ligands: CNCL8 and CCL2 in the supernatant of culture fluid of the 3 kinds of cells and the metastatic tumors., Results: The expression levels of DARC mRNA and protein of the MDA-MB-435HM cells were 38% those of the MDA-MB-435 cells. The expression levels of CXCL8 and CCL2 of the MDA-MB-435HM-DARC cells were significantly lower than those of the MDA-MB-435HM-vect cells and MDA-MB-435HM cells (both P < 0.05). All mice developed tumor with a tumorigenesis rate of 100%. However, the tumor occurred 17 days after implantation in those mice implanted with MDA-MB-435HM-DARC cells, significantly later then in those implanted with MDA-MB-435HM-vect cells and MDA-MB-435HM cells (9 and 10 days after implantation) the size of tumor in the former group being significantly smaller than those of the 2 latter groups (both P < 0.01). The number of metastatic foci in the lung of the MDA-MB-435HM-DARC group was significantly less than those of the other 2 groups (both P < 0.01). The level of CCI2 of the implanted tumor in the MDA-MB-435HM-DARC group was significantly lower than those of the other 2 groups (both P < 0.01). The MVD of the MDA-MB-435HM-DARC was significantly less than those of the other 2 groups (both P < 0.01) and most of the vessels of the MDA-MB-435HM-DARC group were not newly formed vessels with a diameter < 8 red blood cells. The MMP-9 protein expression levels of the MDA-MB-435HM-vect cells and MDA-MB-435HM-cells were 3.1 and 3.4 times that of the MDA-MB-435HM-DARC group (both P < 0.05)., Conclusion: DARC, a chemokine decoy receptor, inhibits the chemokine-induced angiogenesis, thus inhibiting the growth and lung metastasis of breast cancer.