BackgroundSyndecan binding protein (SDCBP), an adapter protein containing PDZ domains, contributes to the tumorigenicity and metastasis of many malignant tumors, such as malignant melanoma. Our study aimed in revealing the expression profile of SDCBP in breast cancer (BCa) and its role in tumor cell proliferation, and then exploring its value in the targeted treatment of BCa.Methodology/Principal FindingsWe first evaluated the SDCBP expression by immunohistochemistry in normal breast and BCa tissues. Then we explored the expression profile of SDCBP in different BCa cell lines. By constructing SDCBP-silenced BCa cell clones, we further assessed the effects of SDCBP suppression on tumor cells in vitro by cell culture and in vivo by tumorigenicity. SDCBP expression was detected in 80.6% (n = 160) of BCa tissues, in contrast to its expression in 13% (n = 23) of normal breast tissues (P<0.001). Among the tumors, the level of its expression was positively correlated with histological grade and tumor staging while negatively correlated with the estrogen receptor (ER) expression. Higher expression of SDCBP was also noted in ER-negative BCa cell lines. It was also identified that SDCBP expression was down-regulated in a dose-dependent mode by 17-β estradiol in estrogen-responsive MCF-7. Furthermore, SDCBP silence inhibited ER-negative tumor cell growth in vivo and in vitro. Cell cycle studies showed that SDCBP silence increased G1 cell population and resulted in related cell-cycle-regulator changes: up-regulation of p21 and p27 while down-regulation of cyclin E.Conclusion/SignificanceOur results suggested that SDCBP played an important role in tumor growth of ER-negative BCas. In these tumors where the estrogen signaling pathway is not available, SDCBP probably contribute to tumor growth through an alternative signaling pathway by promoting tumor cells passing the G1/S checkpoint into the cell cycle. Suppression of SDCBP expression may have its potential to become a targeted therapy for ER-negative BCas.

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Triple negative breast cancer (TNBC) progresses rapidly but lacks effective targeted therapies. Our previous study showed that downregulating syndecan-binding protein (SDCBP) in TNBC inhibits the proliferation of TNBC cells. Dasatinib is a new small-molecule inhibitor of c-src phosphorylation. The aim of this study was to investigate if SDCBP is a potential marker to indicate whether a TNBC is suitable for dasatinib therapy. This study applied co-immunoprecipitation to identify the interaction between SDCBP and c-src in TNBC cell lines. In addition, immunohistochemistry was used to investigate SDCBP and tyrosine-419 phosphorylated c-src (p-c-src-Y419) expression in TNBC tissues. SDCBP-overexpressing MDA-MB-231 cells were then constructed to evaluate the effects of dasatinib on SDCBP-induced TNBC progression in vitro and tumor formation in nude mice. We found wild-type SDCBP interacted with c-src and promoted the phosphorylation of c-src; this phosphorylation was completely blocked by dasatinib. SDCBP lacking the PDZ domain had no such effect. Among the 52 consecutive random TNBC cases examined, the expression of SDCBP was consistent with that of p-c-src-Y419, and positively correlated with histological grading or Ki-67 levels. SDCBP overexpression significantly accelerated the proliferation and cell cycle progression of the TNBC cell line MDA-MB-231; these effects were prevented by dasatinib treatment. However, the subsequent inhibition of p27 expression partially restored the proliferation and viability of the TNBC cells. The results of this study suggest that SDCBP interacts with c-src, regulates G1/S in TNBC cells, and enhances tumor cell proliferation by promoting the tyrosine phosphorylation of c-src at residue 419. Dasatinib inhibits such phosphorylation and blocks SDCBP-induced cell cycle progression. Therefore, SDCBP might be an important marker for identifying TNBC cases that are suitable for dasatinib therapy.

We showed that uMtCK could be easily detected in CM of LNCaP lineaged AIPC cells. Exogenous uMtCK in LNCaP cells surprisingly contributed to overproduction of ROS, activation of Akt signaling pathway and more aggressive phenotypes including androgen independence development.

Radiation therapy is a relatively effective therapeutic method for localized prostate cancer (PCa) patients. However, radioresistance occurs in nearly 30% of patients treated with potentially curative doses. Therapeutic synergy between radiotherapy and androgen ablation treatment provides a promising strategy for improving the clinical outcome. Accordingly, the androgen deprivation-induced signaling pathway may also mediate radiosensitivity in PCa cells. The C4-2 cell line was derived from the androgen-sensitive LNCaP parent line under androgen-depleted condition and had acquired androgen-refractory characteristics. In our study, the response to radiation was evaluated in both LNCaP and C4-2. Results showed that C4-2 cells were more likely to survive from irradiation and appeared more aggressive in their resistance to radiation treatment compared with LNCaP, as measured by clonogenic assays and cell viability and cell cycle analyses. Gene expression analyses revealed that a set of genes involved in cell cycle arrest and DNA repair were differentially regulated in LNCaP and C4-2 in response to radiation, which was also consistent with the radiation-resistant property observed in C4-2 cells. These results strongly suggested that the radiation-resistant property may develop with progression of PCa to androgen-independent status. Not only can the LNCaP and C4-2 PCa progression model be applied for investigating androgen-refractory progression, but it can also be used to explore the development of radiation resistance in PCa.

Dual-probe fluorescence in situ hybridization (D-FISH) is a widely accepted method to determine the gene amplification status of human epidermal growth factor receptor 2 (Her-2). In 2013, the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) updated the guidelines on the Her-2 testing for invasive breast cancer (BCa). The interpretation criteria for D-FISH changed accordingly. In this study, we compared the Her-2 FISH statuses based on the 2013 and 2007 ASCO/CAP guidelines in 1931 cases of BCa with Her-2 D-FISH testing at our hospital. We analyzed the clinicopathologic features of cases with equivocal results by the 2013 ASCO/CAP guidelines. Although the guideline update significantly improved the detection rate of Her-2 amplification, it also significantly increased the rate of equivocal results, posing a dilemma for clinical management. The equivocal results had good reproducibility. The distribution of D-FISH equivocal cases did not correlate with Her-2 status by immunohistochemistry, suggesting that Her-2 D-FISH equivocality may not reflect Her-2 overexpression. Compared with Her-2 negative cases by D-FISH, Her-2 D-FISH equivocal cases had higher Ki-67 expression, higher histological grade, more frequent lymph node metastasis, and lower estrogen receptor α expression, indicating a group of BCa with worse prognosis. The clinical significance of Her-2 equivocal results by D-FISH warrants further investigation.

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PC-1(Prostate and colon gene 1) gene belongs to TPD52 (Tumor Protein D52) gene family. The expression of PC-1 is found to promote androgen-independent progression. This study was conducted to assess the mechnism of promotion of androgen-independent progression in PC-1 gene. The c-myc gene expression was tested by RT-PCR and Western blotting analyses in the LNCaP-pc-1 and LNCaP-zero cell line. After separation of cytoplasm and nulear proteins of the LNCaP-pc-1 and LNCaP-zero cell line, the beta-catenin protein was detected by Western blotting. C4-2 cell line was used to examine the effects of 10058-F4 on the PC-1 gene expression. The results of RT-PCR and Western blotting indicated that PC-1 enhanced c-myc gene expression in prostate cancer cells, PC-1 was also found to enhance beta-catenin expression in nuclear. Furthermore, a small-molecule c-Myc inhibitor, 10058-F4 represses PC-1 gene expression in C4-2 cell line. Our findings suggest that PC-1 enhances c-myc gene expression in prostate cancer cells through the Wnt/beta-catenin pathway. Meanwhile, c-myc plays a feed-forward role in enhancing PC-1 driven c-myc gene expression, and promotes prostate an-drogen-independent progression.