MicroRNA-137 inhibits BMP7 to enhance the epithelial-mesenchymal transition of breast cancer cells.

Bone morphogenetic protein-7 (BMP7) is known to antagonize transforming growth factor ß 1 (TGFß1)-mediated fibrosis through suppressing epithelial-mesenchymal transition (EMT). We recently reported that BMP7 also antagonizes the effects of TGFß1 in breast cancer (BC) tumorigenesis-related EMT. Nevertheless, the control of BMP7 expression in BC remains ill-defined. Here, we detected significantly lower levels of BMP7 and significantly higher levels of microRNA-137 (miR-137) in the BC specimens, relative to paired adjacent non-tumor breast tissue. BMP7 and miR-137 levels were correlated inversely. Additionally, the high miR-137 levels in BC specimens were correlated with reduced patient survival. In vitro, overexpression of miR-137 significantly increased cell EMT and invasion, while depletion of miR-137 significantly decreased cell EMT and invasion in BC cells. The increases in BC cell invasiveness by miR-137 appeared to result from its suppression of BMP7, through direct binding of miR-137 to the 3'-UTR of BMP7 mRNA, thereby blocking its protein translation in BC cells. This study sheds light on miR-137 as a crucial factor that enhances BC cell EMT and invasiveness, and points to miR-137 as a promising innovative therapeutic target for BC treatment.

Lycorine inhibits breast cancer growth and metastasis via inducing apoptosis and blocking Src/FAK-involved pathway.

Breast cancer is the most commonly diagnosed cancer type worldwide among women and more than 90% of patients die from tumor metastasis. Lycorine, a natural alkaloid, has been widely reported possessing potential efficacy against cancer proliferation and metastasis. In our study, the anti-tumor potency on breast cancer was evaluated in vitro and in vivo for the first time. Our results indicated that lycorine inhibited breast cancer cells growth, migration and invasion as well as induced their apoptosis. In in vivo study, lycorine not only suppressed breast tumor growth in xenograft models and inhibited breast tumor metastasis in MDA-MB-231 tail vein model. More importantly, we found lycorine had less toxicity than first-line chemotherapy drug paclitaxel at the same effective dose in vivo. Furthermore, on mechanism, lycorine inhibited tumor cell migration and invasion via blocking the Src/FAK (focal adhesion kinase)-involved pathway. In conclusion, our study implied lycorine was a potential candidate for the treatment of breast cancer by inhibition of tumor growth and metastasis.

A novel synthetic small molecule YF-452 inhibits tumor growth through antiangiogenesis by suppressing VEGF receptor 2 signaling.

Tumor angiogenesis is characterized by abnormal vessel morphology, endowing tumor with highly hypoxia and unresponsive toward treatment. To date, mounting angiogenic factors have been discovered as therapeutic targets in antiangiogenic drug development. Among them, vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors exerts potent antiangiogenic activity in tumor therapy. Therefore, it may provide a valid strategy for cancer treatment through targeting the tumor angiogenesis via VEGFR2 pathway. In this study, we established a high-profile compounds library and certificated a novel compound named N-(N-pyrrolidylacetyl)-9-(4-bromobenzyl)-1,3,4,9-tetrahydro-ß-carboline (YF-452), which remarkably inhibited the migration, invasion and tube-like structure formation of human umbilical vein endothelial cells (HUVECs) with little toxicity invitro. Rat thoracic aorta ring assay indicated that YF-452 significantly blocked the formation of microvascular exvivo. In addition, YF-452 inhibited angiogenesis in chick chorioallantoic membrane (CAM) and mouse corneal micropocket assays. Moreover, YF-452 remarkably suppressed tumor growth in xenografts mice model. Furthermore, investigation of molecular mechanism revealed that YF-452 inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including extracellular signal regulated kinase (ERK), focal adhesion kinase (FAK) and Src. These results indicate that YF-452 inhibits angiogenesis and may be a potential antiangiogenic drug candidate for cancer therapy.

Bone Morphogenetic Protein-7 Inhibits EMT-Associated Genes in Breast Cancer.

BACKGROUND/AIMS: Bone morphogenetic protein-7 (BMP7) has been shown to reduce the severity of injury-induced fibrosis through counteracting the fibrotic effects of transforming growth factor ß 1 (TGFß1). However, this model in the carcinogenesis of breast cancer is unknown. METHODS: We analyzed the effects of BMP7 and TGFß1 on gene transcripts and protein levels of EMT-related factors in breast cancer cells by RT-qPCR and Western blot, respectively. The effects of BMP7 and TGFß1 on cell invasiveness and migration were evaluated by scratch wound healing assay and transwell cell migration assay. The cell growth was measured by MTT assay. RESULTS: BMP7 did not alter the TGFß1-stimulated phosphorylation of TGFß receptor, but significantly inhibited the TGFß1-activated epithelial-mesenchymal transition (EMT)-related genes in breast cancer cells, resulting in a significant reduction in TGFß1-triggered cell growth and cell metastasis. CONCLUSION: Our data suggest that besides being a well-known antagonist for TGFß1 in fibrosis, BMP7 may also antagonize TGFß1 in tumorigenesis-associated EMT in breast cancer. Thus, BMP7 may be a promising therapeutic target for treating breast cancer.

A comparison of mammography and ultrasound in women with breast disease: a receiver operating characteristic analysis.

The purpose of this study was to compare mammography and sonography, as well as their combination, for detecting breast tumors in symptomatic patients. The effects of age and hormonal status were also examined. From 1999 to 2007, 549 patients underwent 665 examination sessions (mammography and ultrasound). Abnormalities were deemed positive if biopsy findings revealed malignancy and negative if findings from biopsy or all screening examinations were negative. On pathology, 246 lesions were malignant and 419 were benign in the 549 patients. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve (AUC) of mammography and sonography were 81.71% and 95.53%, 85.44% and 80.43%, 76.72% and 74.13%, 88.83% and 96.84%, and 0.886 and 0.948, respectively. The sensitivity and diagnostic accuracy among patients <50 years of age were significantly higher for sonography than for mammography (p < 0.05). The sensitivity and diagnostic accuracy among premenopausal or perimenopausal patients were significantly higher for sonography than for mammography (p < 0.05). The sensitivity among postmenopausal patients was significantly higher for sonography than for mammography (p < 0.05). The results of combined mammography and sonography were classified using American College of Radiology Breast Imaging Reporting and Data System (BI-RADS). There were 244 positive and two negative examinations of malignant lesions, and 106 positive and 313 negative examinations of benign lesions. The diagnostic accuracy of the combination was significantly higher than that of mammography (p < 0.05) and similar to that of sonography (p > 0.05). Sonography had better sensitivity and diagnostic accuracy than mammography for diagnosing breast diseases, while their specificities were similar. The diagnostic accuracy of diagnostic sonography was significantly better than that of mammography among patients <50 years of age and premenopausal or perimenopausal patients. The combination of mammography and sonography increased the sensitivity and diagnostic accuracy.

aPKC inhibitors might be the sensitizer of chemotherapy and adoptive immunotherapy in the treatment of hASIPa-overexpressed breast cancer.

The atypical protein kinase C (aPKC) plays an important role in cell growth through the interaction with its substracts, including human ASIP (hASIP), which contains an aPKC phosphorylation site encoded by exon 17b of the gene. hASIP is expressed as numerous alternative splicing isoforms in the cells. Our results showed that hASIPa, an exon 17b-containing isoform of hASIP, is overexpressed in human breast cancer (HBC) MDA-MB-231, SK-BR-3, and MCF-7 cell lines and HBC specimens. The anticancer effects of 5-FU chemotherapy or adoptive immunotherapy and the synergic action of aPKC inhibitor against hASIPa-overexpressed HBC cells were tested. The results indicated that HBC MDA-MB-231 and SK-BR-3 cells were sensitive to 5-FU treatment in vitro. The combined treatment of aPKC inhibitor and 5-FU raised the anticancer activities against hASIPa-overexpressed HBC cells. The coculture of cytokine-induced killer (CIK) cells and autologous dendritic cells (DCs) with or without Her-2 peptide GP2 pulse created two new populations of effective immune-active T-cell populations called DC-modulated and cytokine-induced killer (DCIK) cells and peptide-DC-modulated and cytokine-induced killer (DCIK-P) cells. The DCIK cells showed cytotoxic activities on MDA-MB-231, SK-BR-3, and MCF-7 cells in MHC unrestricted manner. The DCIK-P cells possessed extra-enhanced cytotoxic activities against HLA-A2+/Her-2+ MDA-MB-231 cells in MHC restricted manner, but not for HLA-A2+/-/Her-2+ SK-BR-3 cells and HLA-A2+/Her-2+/- MCF-7 cells. The data suggested specific cytotoxic T-lymphocyte (CTL) activity of DCIK-P cells on MDA-MB-231 cells. The combined treatment of aPKC inhibitor with DCIK/DCIK-P cells further raised the anticancer activities against hASIPa-overexpressed HBC cells. The results demonstrated that the hASIPa/aPKC signaling pathway functions as an important regulator in the growth of HBC cells and aPKC inhibitor treatment showed the synergic activities on 5-FU or DCIK/DCIK-P cells adoptive immunotherapy against hASIPa-overexpressed HBC cells.