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Triple‐negative breast cancer (TNBC) is a highly aggressive tumour subtype associated with poor prognosis. The mechanisms involved in TNBC progression remains largely unknown. To date, there are no effective therapeutic targets for this tumour subtype. Paired‐related homeobox 1b (Prrx1b), one of major isoforms of Prrx1, has been identified as a new epithelial–mesenchymal transition (EMT) inducer. However, the function of Prrx1b in TNBC has not been elucidated. In this study, we found that Prrx1b was significantly up‐regulated in TNBC and associated with tumour size and vascular invasion of breast cancer. Silencing of Prrx1b suppressed the proliferation, migration and invasion of basal‐like cancer cells. Moreover, silencing of Prrx1b prevented Wnt/β‐catenin signaling pathway and induced the mesenchymal‐epithelial transition (MET). Taken together, our data indicated that Prrx1b may be an important regulator of EMT in TNBC cells and a new therapeutic target for interventions against TNBC invasion and metastasis.

Background/Aims: Epithelial-mesenchymal transition (EMT) is recognized as a crucial mechanism in breast cancer progression and metastasis. Paired-related homeobox 2 (Prrx2) has been identified as a new EMT inducer in cancer, but the underlying mechanisms are still poorly understood. Methods: The expression of Prrx2 was assessed by immunohistochemistry in breast cancer tissues to evaluate the clinicopathological significance of Prrx2, as well as the correlation between Prrx2 and EMT. Short hairpin RNA knockdown of Prrx2 was used to examine cellular effects of Prrx2, detecte the expression of Wnt/β-catenin signaling and EMT-associated proteins, and observe cell proliferation, invasion and migration abilities in vitro and in vivo . Results: Clinical association studies showed that Prrx2 expression was related to tumor size, lymph node metastasis, tumor node metastasis stages, EMT and poor survival. Results also showed that knockdown of Prrx2 could alter cell morphology, suppressed the abilities of cell proliferation, invasion and migration in breast cancer. Moreover, silencing of Prrx2 induced the mesenchymal-epithelial transition and prevented nuclear translocation of β-catenin, inhibited wnt/β-catenin signaling pathway. Conclusion: Our study indicated that Prrx2 may be an important activator of EMT in human breast cancer and it can serve as a molecular target of therapeutic interventions for breast cancer.

BACKGROUND Lipid synthesis is an integrated result of genetic, epigenetic and environmental factors, and also can promote growth and survival of cancer cells. Apolipoprotein B plays a central role in lipid metabolism as the major protein component of very-low-density lipoprotein and low-density lipoprotein. METHODS We investigated the associations of polymorphisms of rs693 (-7673C>T) and rs1042031 (-12669 G>A) in the APOB gene with risk of breast cancer in 675 blood-unrelated Chinese patients with breast cancer and 712 healthy controls. RESULTS Polymorphisms of -12669 G>A and -7673C>T in the APOB gene were significantly associated with an increased risk of breast cancer (P = 0.000), especially for postmenopausal women (P = 0.000, 0.023). The positive associations still remained after further analysis of the two polymorphisms' distribution according to body mass index. However, no statistical associations were found between -12669 G>A and -7673C>T polymorphisms and other clinical characteristics, including tumor size, lymph node metastasis, histological grade, estrogen and progesterone receptor status and Her-2 status. CONCLUSIONS rs693 and rs1042031 polymorphisms in the APOB gene increased the risk of breast cancer in Chinese, and this role of the two polymorphisms in connection with breast cancer was not dependent on body mass index.

Breast cancer in young women younger than 35 years old is rare, aggressive and associated with a poor prognosis. Endocrine therapy is a preferred treatment modality in hormone receptor-positive early stage and advanced breast cancer, combined therapy of goserelin and letrozole presents an option for premenopausal women. We reported the efficacy and safety of therapy of goserelin plus letrozole on very young women with advanced breast cancer as first-line endocrine therapy. Thirty-five patients with first diagnosed as advanced breast cancer, age younger than 35 years, were enrolled in the study. All patients received goserelin 3.6 mg by subcutaneous injection every 4 weeks along with letrozole 2.5mg daily by mouth as first-line endocrine therapy. The study endpoints were objective response rate (ORR), clinical benefit (CB), progression-free survival (PFS), overall survival (OS) and toxicity. The median duration of response to the therapy was 21 (range, 10-56) months, and median duration of follow-up was 44 (range, 5-79) months. The ORR was 25.7%, with one complete response (CR, 2.9%) and eight partial response (PR, 22.9%). Twenty-two patients had stable disease at 24 weeks, for a clinical benefit rate of 65.7%. The median PFS was 9.6 (range 5-58) months and median OS was 33 (range 6-72) months. During the therapy and follow-up, no serious toxicities were reported. Combined therapy of goserelin and letrozole appears to be an efficacious and well-tolerated therapy for very young women with advanced breast cancer. Further investigations involving more patients, combination of other therapies and longer follow-up are requisite.

The ability of immune system to react specifically against tumors inspirited the study of triple negative breast cancer (TNBC) immunotherapies. Sixty spontaneous breast cancer TA2 mice were randomly divided into three groups: GM-CSF group, with therapy of granulocyte-macrophage colony-stimulating factor (GM-CSF) combined with breast cancer stem cells associated antigens and cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG-ODNs); DC-CIK group, with infusions of dendritic cells/cytokine-induced killer (DC/CIK) cells; and PBS group as controls. After therapy, the cellular immunity of mice in GM-CSF group and DC-CIK group was obviously increased, especially for GM-CSF group (P

Peritoneal metastases are one reason for the poor prognosis of scirrhous gastric cancer (SGC), and myofibroblast provides a favorable environment for the peritoneal dissemination of gastric cancer. The aim of this study was to determine whether myofibroblast originates from peritoneal mesothelial cells under the influence of the tumor microenvironment. Immunohistochemical studies of peritoneal biopsy specimens from patients with peritoneal lavage cytological (+) status demonstrate the expression of the epithelial markers cytokeratin in fibroblast-like cells entrapped in the stroma, suggesting that these cells stemmed from local conversion of mesothelial cells. To confirm this hypothesis in vitro, we co-incubated mesothelial cells with SGC or non-SGC to investigate morphology and function changes. As we expected, mesothelial cells undergo a transition from an epithelial phenotype to a mesenchymal phenotype with loss of epithelial morphology and decrease in the expression of cytokeratin and E-cadherin when exposed to conditioned medium from HSC-39, and the induction of mesothelial cells can be abolished using a neutralizing antibody to transforming growth factor-beta1 (TGF-β1) as well as by pre-treatment with SB431542. Moreover, we found that these mesothelial cells-derived cells exhibit functional properties of myofibroblasts, including the ability to increase adhesion and invasion of SGC. In summary, our current data demonstrated that mesothelial cells are a source of myofibroblasts under the SGC microenvironment which provide a favorable environment for the dissemination of gastric cancer; TGF-β1 produced by autocrine/paracrine in peritoneal cavity may play a central role in this pathogenesis.

Metastasis is unequivocally the most lethal aspect of breast cancer and the most prominent feature associated with disease recurrence, the molecular mechanisms whereby epithelial-to-mesenchymal transition (EMT) mediates the initiation and resolution of breast cancer metastasis remains poorly understood. Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine that is intimately involved in regulating numerous physiological processes, including cellular differentiation, homeostasis and EMT. Recent findings have implicated high levels of TGF-β1 were associated with poor outcome, whereas inhibition of TGF-β signaling reduces metastasis in breast cancer, suggesting that the chemo-therapeutic targeting of TGF-β1 or TGF-β signaling may offer new inroads in ameliorating metastatic disease in breast cancer patients. In this study, we showed immunohistochemical evidence for EMT, which is associated with TGF-β1 expression, at the invasion front of breast cancer in vivo. The data also indicated that human breast cancer cell lines, MCF-7 and MDA-MB-435S, of epithelial cell characteristics were induced to undergo EMT by TGF-β1 and dependent on the Smad2 signaling pathway. Following TGF-β1 treatment, cells showed dramatic morphological changes assessed by phase contrast microscopy, accompanied by decreased epithelial marker and increased mesenchymal markers. Importantly, cell invasion was also enhanced in the EMT process, while knockdown of the Smad2 gene by silencing siRNA partially inhibited these effects in MDA-MB435S (P

Peritoneal dissemination is one of the main causes of death in gastric cancer patients. Our previous study demonstrated that peritoneal fibrosis induced by transforming growth factor-β1 (TGF-β1) may provide a favorable environment for the dissemination of gastric cancer. The role of Smad3 in the development of dermal fibrosis, subcapsular cataract, and peritoneal fibrosis has been reported. However, the potential role of Smad2 in the development of fibrosis is unclear. The objective of this study was to determine the effect of Smad2 in peritoneal fibrosis, induced by TGF-β1, on dissemination of gastric cancer. Here we demonstrate that TGF-β1 significantly stimulated the expression of collagen III and fibronectin in mesothelial cells through the Smad2 signal transduction pathway, but knockdown of the Smad2 gene by silencing siRNA partially inhibited these effects. This inhibition was associated with a depressed adhesion and invasiveness of gastric cancer cells. We conclude that peritoneal fibrosis induced by TGF-β1 is dependent on Smad2 signaling and may provide a hospitable environment for carcinomatosis.