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<0.05). These data suggested that EMT of breast cancer induced by TGF-β1 is dependent on Smad2 signaling and promotes breast cancer cell metastasis.

The tremendous improvement of survival in patients with breast cancer can be attributed to several treatment strategies, but these strategies also lead to the occurrence of breast cancer-related lymphedema (BCRL). BRCL is regularly associated with factors such as axillary lymph node dissection and local lymph node radiotherapy and manifests as an increase of >10% in the volume of affected limbs. Being overweight or having obesity (body mass index ≥25 kg/m 2 ), an excessive number of positive lymph nodes (>8) and capsular invasion by a tumor are additional risk factors for lymphedema. It is worth assessing the risk before surgery as this can prevent the occurrence of BCRL at the initial stage of breast cancer management. The clinical utility of many diagnostic tools and lymphedema surveillance allows early stage and even subclinical BCRL to be diagnosed, and allows real-time monitoring of the disease. The early diagnosis of BRCL allows treatment at an early stage, which is beneficial to the reduction of excess limb volume and the improvement of quality of life. At present, the major therapeutic methods of BCRL include complex decongestive therapy, pneumatic compression devices, participating in exercise, microsurgery and liposuction, each of which alleviates lymphedema effectively. No medications for treatment of BRCL have yet been developed. However, the recent findings on the success of molecular therapy in animal models may remedy this deficiency. Furthermore, the volume reduction of swollen limbs without swelling rebound by transplanting autologous stem cells has been successfully reported in some pilot studies, which may provide a new technique for treating BCRL. This review aimed to discuss the pathogenesis, clinical manifestation, risk factors, advantages and disadvantages of diagnostic tools, lymphedema surveillance and the characteristics of traditional and newly emerging BCRL treatments.

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.

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.

Although breAst cAncer is the most common cancer in women in the developing and developed countries, only 1% of the patients are younger than 35 years old [1]. Breast cancer in young women is considered aggressive and associated with a poor prognosis [2,3]. Earlier data from the Finnish Cancer Registry in the 1990's showed that very young women had a more advanced breast cancer at diagnosis and poorer 5-year survival than older premenopausal patients [4]. Recent data indicated the 5-year overall survival (OS) for young women had been better but is still lower than for all breast cancer patients, and disease free interval (DFI) was shorter in patients with hormone receptor positive disease [1].Endocrine therapy is the preferred treatment modality in hormone-receptor-positive (HR) early stage and Abstract. 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 3.6mg 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.