4D Structural Evolution of the West Niger Delta Deepwater Fold and Thrust Belt

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Fascin Is a Key Regulator of Breast Cancer Invasion That Acts via the Modification of Metastasis-Associated Molecules

The actin-bundling protein, fascin, is a member of the cytoskeletal protein family that has restricted expression in specialized normal cells. However, many studies have reported the induction of this protein in various transformed cells including breast cancer cells. While the role of fascin in the regulation of breast cancer cell migration has been previously shown, the underlying molecular mechanism remained poorly defined. We have used variety of immunological and functional assays to study whether fascin regulates breast cancer metastasis-associated molecules. In this report we found a direct relationship between fascin expression in breast cancer patients and; metastasis and shorter disease-free survival. Most importantly, in vitro interference with fascin expression by loss or gain of function demonstrates a central role for this protein in regulating the cell morphology, migration and invasion potential. Our results show that fascin regulation of invasion is mediated via modulating several metastasis-associated genes. We show for the first time that fascin down-regulates the expression and nuclear translocation of a key metastasis suppressor protein known as breast cancer metastasis suppressor-1 (BRMS1). In addition, fascin up-regulates NF-kappa B activity, which is essential for metastasis. Importantly, fascin up-regulates other proteins that are known to be critical for the execution of metastasis such as urokinase-type plasminogen activator (uPA) and the matrix metalloproteases (MMP)-2 and MMP-9. This study demonstrates that fascin expression in breast cancer cells establishes a gene expression profile consistent with metastatic tumors and offers a potential therapeutic intervention in metastatic breast cancer treatment through fascin targeting

ALK alteration is a frequent event in aggressive breast cancers

Introduction: Breast cancer is the most common female malignancy worldwide and, despite improvements in treatment modalities, there are increased chances of recurrence and metastasis in a substantial number of cases and it remains one of the major causes of mortality among female cancer patients. Anaplastic lymphoma kinase (ALK) gene has been found to be altered in several solid and hematologic tumors. We aimed to comprehensively study the prevalence of ALK expression, and changes in copy number and translocation in a large cohort of breast cancer cases in a Middle Eastern population. Methods: ALK protein expression was investigated by immunohistochemistry and numerical and structural variations of the ALK gene were analyzed by fluorescence in situ hybridization (FISH) in a tissue microarray format in a cohort of more than 1000 Middle Eastern breast cancers. The data were correlated with clinicopathologic parameters and other important molecular biomarkers.Results: Immunohistochemical analysis showed ALK overexpression in 36.0 % of the breast cancer patients and gene amplification was present in 13.3 % of cases, seen by FISH analyses. ALK overexpression was significantly associated with ALK gene amplification (p = 0.0031). ALK-overexpressing tumors showed significant association with high-grade tumors (p = 0.0039), ductal histologic subtype (p = 0.0076), triple-negative phenotype (p = 0.0034), and high Ki-67 (p = 0.0001) and p-AKT (p \u3c0.0001). Conclusions: Immunohistochemical analysis showed ALK is overexpressed in a substantial proportion of breast cancers and possibly plays a significant role in the aggressive behavior of this cancer. Gene amplification is hypothesized to be a possible cause for a significant proportion of this overexpression. Based on these findings, a potential role for an ALK inhibitor, as a therapeutic agent targeting aggressive subtypes of breast cancer, merits further investigation

Factors that predict early treatment failure for patients with locally advanced (T4) breast cancer

Locally advanced breast cancer (LABC) is associated with dire prognosis despite progress in multimodal treatments. We evaluated several clinical and pathological features of patients with either noninflammatory (NIBC, cT4a-c) or inflammatory (IBC, cT4d) breast cancer to identify subset groups of patients with high risk of early treatment failure. Clinical and pathological features of 248 patients with LABC, who were treated with multimodality treatments including neoadjuvant chemotherapy followed by radical surgery and radiotherapy were reassessed. Tumour samples obtained at surgery were evaluated using standard immunohistochemical methods. Overall, 141 patients (57%) presented with NIBC (cT4a-c, N0-2, M0) and 107 patients (43%) with IBC (cT4d, N0-2, M0). Median follow-up time was 27.5 months (range: 1.6–87.8). No significant difference in terms of recurrence-free survival (RFS) (P=0.72), disease-free survival (DFS) (P=0.98) and overall survival (OS) (P=0.35) was observed between NIBC and IBC. At the multivariate analysis, patients with ER- and PgR-negative diseases had a significantly worse RFS than patients with ER- and/or PgR-positive diseases (hazard ratio: 2.47, 95% CI: 1.33–4.59 for overall). The worst RFS was observed for the subgroup of patients with endocrine nonresponsive and HER2-negative breast cancer (2-year RFS: 57% in NIBC and 57% in IBC) A high Ki-67 labelling index (>20% of the invasive tumour cells) and the presence of peritumoral vascular invasion (PVI) significantly correlated with poorer RFS in overall (HR 2.69, 95% CI: 1.61–4.50 for Ki-67>20% and HR 2.27, 95% CI: 1.42–3.62 for PVI). Patients with endocrine nonresponsive LABC had the most dire treatment outcome. High degree of Ki-67 staining and presence of PVI were also indicators of higher risk of early relapse. These factors should be considered in therapeutic algorithms for LABC

FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy

<p>Abstract</p> <p>Background</p> <p>Recent studies have demonstrated a direct involvement of B7-H1, PD-1 and FOXP3 molecules in the immune escape of cancer. B7-H1 is an inhibitory molecule that binds to PD-1 on T lymphocytes, while FOXP3 is a marker for regulatory T cells (T_regs). We have previously demonstrated the association of B7-H1-expressing T infiltrating lymphocytes (TIL) with high-risk breast cancer patients while other studies reported the involvement of FOXP3+ T_regsas a bad prognostic factor in breast tumors. Although the co-existence between the two types of cells has been demonstrated <it>in vitro </it>and animal models, their relative infiltration and correlation with the clinicopathological parameters of cancer patients have not been well studied. Therefore, we investigated TIL-expressing the B7-H1, PD-1, and FOXP3 molecules, in the microenvironment of human breast tumors and their possible association with the progression of the disease.</p> <p>Methods</p> <p>Using immunohistochemistry, tumor sections from 62 breast cancer patients were co-stained for B7-H1, PD-1 and FOXP3 molecules and their expression was statistically correlated with factors known to be involved in the progression of the disease.</p> <p>Results</p> <p>A co-existence of B7-H1⁺T lymphocytes and FOXP3⁺T_regswas evidenced by the highly significant correlation of these molecules (<it>P </it>< .0001) and their expression by different T lymphocyte subsets was clearly demonstrated. Interestingly, concomitant presence of FOXP3⁺T_regs, B7-H1⁺and PD-1⁺TIL synergistically correlated with high histological grade (III) (<it>P </it>< .001), estrogen receptor negative status (<it>P </it>= .017), and the presence of severe lymphocytic infiltration (<it>P </it>= .022).</p> <p>Conclusion</p> <p>Accumulation of TIL-expressing such inhibitory molecules may deteriorate the immunity of high-risk breast cancer patients and this should encourage vigorous combinatorial immunotherapeutic approaches targeting T_regsand B7-H1/PD-1 molecules.</p