Although breast cancer is the second most common cause of central nervous system (CNS) metastases with a notable increase of incidence, only few studies on brain-metastasizing breast cancer are available. In this immunohistochemical and fluorescence in situ hybridization (FISH) study, metastases to the CNS (n ¼ 85) and primary breast cancers, with known involvement of the CNS (n ¼ 44) including paired primary and metastasized tumours (n ¼ 23), were investigated retrospectively for the expression of oestrogen-(ER) and progesterone-(PR) hormone receptors, Her-2/neu, epidermal growth factor receptor (EGFR), Ki-67, and cytokeratins (CKs) 5/ 14. The majority of brain metastases were steroid hormone receptor negative (ER 66%, PR 82%) corresponding to the findings in primary tumours with known involvement of the CNS (68% ER-negative, 75% PR-negative). The frequency of HER-2/neu-overexpressing or -amplified cancers was increased in both groups (34 and 32%, respectively). EGFR expression was more frequent in metastases (41%) than in primary tumours (16%). The proportions of cases with a basal phenotype were 26 and 30%, respectively. In paired primary tumours and metastases to the CNS, constancy of Her-2/neu status was observed in 87% of cases with only one sample turning Her-2/neu-negative and two samples acquiring overexpression/amplification in brain metastases. In contrast, steroid hormone receptors exhibited more frequently a loss of expression (17%) than a gain (9%) with 74% revealing a constant phenotype. We conclude that brain-metastasizing breast cancer belongs predominantly to the basal type or Her-2/neu type. Primary and metastatic tumours differ from each other only in a minority of cases, leading rather to a loss of steroid hormone receptors and to a gain of EGFR and Her-2/neu.
Invasive tumor cells and their microenvironments are enriched with a broad spectrum of different proteases. Legumain, a novel asparaginyl endopeptidase, has been observed to be highly expressed in several types of solid tumors. However, there is no data available identifying the relationship of legumain expression and clinicopathologic or biological variables in invasive breast cancer. For the first time, the prevalence of legumain expression in invasive breast cancer (n = 432) and non-neoplastic breast tissues (n = 128) was investigated by immunohistochemistry. Three staining patterns were observed in the cytoplasm: diffuse positivity, tiny dots and vesicles. Whereas vesicular positivity in the majority of tumor cells was significantly correlated to an adverse outcome, cytoplasmic and dot-like staining showed no prognostic effect. Vesicular positivity was observed in 24% of carcinomas, but only in one case of non-neoplastic breast tissue (<1%; proliferative mastopathy). This staining pattern was found to be independent of other factors analysed as grading, nodal status or HER2 expression. Besides being of prognostic value, legumain might prove to be an important predictive factor in breast cancer, since its unique cleavage specificity is already used in prodrug activation strategies.
Purpose: Invasive ductal carcinoma and invasive lobular carcinoma (ILC) represent the major histologic subtypes of invasive breast cancer. They differ with regard to presentation, metastatic spread, and epidemiologic features. To elucidate the genetic basis of these differences, we analyzed copy number imbalances that differentiate the histologic subtypes. Experimental Design: High-resolution genomic profiling of 40 invasive breast cancers using matrix-comparative genomic hybridization with an average resolution of 0.5 Mb was conducted on bacterial artificial chromosome microarrays. The data were subjected to classification and unsupervised hierarchical cluster analyses. Expression of candidate genes was analyzed in tumor samples. Results:The highest discriminating power was achieved when combining the aberration patterns of chromosome arms 1q and16p, which were significantly more often gained in ILC.These regions were further narrowed down to subregions 1q24.2-25.1, 1q25.3-q31.3, and 16p11.2. Located within the candidate gains on 1q are two genes, FMO2 and PTGS2, known to be overexpressed in ILC relative to invasive ductal carcinoma. Assessment of four candidate genes on 16p11.2 by real-time quantitative PCR revealed significant overexpression of FUS and ITGAX in ILC with 16p copy number gain. Unsupervised hierarchical cluster analysis identified three molecular subgroups that are characterized by different aberration patterns, in particular concerning gain of MYC (8q24) and the identified candidate regions on 1q24.2-25.1, 1q25.3-q31.3, and 16p11.2. These genetic subgroups differed with regard to histology, tumor grading, frequency of alterations, and estrogen receptor expression. Conclusions: Molecular profiling using bacterial artificial chromosome arrays identified DNA copy number imbalances on 1q and 16p as significant classifiers of histologic and molecular subgroups.Invasive ductal carcinoma (IDC) represents the predominant histologic subtype of breast cancer, constituting 40% to 75% of mammary carcinomas, whereas invasive lobular carcinoma (ILC) ranges second in frequency and accounts for 5% to 15% of cases. Besides differences in the histopathologic morphology, ILC and IDC differ with regard to clinical and epidemiologic features. There has been a steady and disproportionate increase in the incidence of ILC compared with IDC in women over 50 years during the last 20 years, which has been attributed to the increased use of hormone replacement therapy (1, 2). The molecular basis for this development as well as for differences in phenotype and clinical behavior between ILC and IDC is not yet understood.The molecular portrait of breast cancer was previously explored by a number of groups (3, 4), with two recent studies specifically comparing the gene expression profiles of IDC and ILC (5,6). Using unsupervised cluster analysis, Zhoa et al. (5) were able to subdivide ILC into a ''typical'' and a ''ductal-like'' subgroup. The typical ILC showed expression patterns similar to those of tumors that p...
Background/Aims: Peritoneal carcinomatosis, which is caused by the dissemination of cancer cells into the abdominal cavity is a frequent finding in patients with primary gastric cancer, and it is associated with a poor prognosis. The mechanisms that mediate peritoneal carcinomatosis in diffuse primary gastric tumours require definition. Methods: We therefore compared the gene expression profile in diffuse primary gastric cancer patients with and without peritoneal carcinomatosis (n=13). Human specimens from consecutive gastric cancer patients with and without peritoneal carcinomatosis were investigated using oligonucleotide microarrays. Differentially expressed genes of interest were further evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). Results: The results reveal a significant overexpression of phosphoglycerate kinase 1 (PGK1), the chemokine CXCR4 and its ligand CXCL12 in specimens from diffuse gastric cancer patients with peritoneal carcinomatosis. Overexpression of PGK1 is known to increase the expression of CXCR4. CXCR4 on its part can increase CXCL12 expression. Elevated levels of CXCR4 and CXCL12 are associated with an increase in the metastatic rate and play an important role in the metastatic homing of malignant cells. Conclusion: The overexpression of PGK1 and its signalling targets may be a expression-pathway in diffuse primary gastric carcinomas promoting peritoneal dissemination and may function as prognostic markers and/or be potential therapeutic targets to prevent the migration of gastric carcinoma cells into the peritoneum.
Peritoneal carcinomatosis is a frequent finding in gastric cancer associated with a poor prognosis. The features that enable gastric tumors to disseminate are poorly understood until now. Previously, we showed elevated mRNA levels of phosphoglycerate kinase 1 (PGK1), an adenosine triphosphate‐generating enzyme in the glycolytic pathway, the chemokine receptor 4 (CXCR4), the corresponding chemokine ligand 12 (CXCL12) and β‐catenin in specimens from gastric cancer patients with peritoneal carcinomatosis. In this study, the influence of PGK1 on CXCR4 and β‐catenin was assessed as well as the invasiveness of PGK1 overexpressing cancer cells. In this current study, we found that PGK1 regulates the expression of CXCR4 and β‐catenin at the mRNA and protein levels. On the other hand, CXCR4 regulates the expression of PGK1. Plasmid‐mediated overexpression of PGK1 dramatically increased the invasiveness of gastric cancer cells. Interestingly, inhibition of CXCR4 in cells overexpressing PGK1 produced only a moderate reduction of invasiveness suggesting that, PGK1 itself has a critical role in tumor invasiveness. Immunohistochemistry in specimens from diffuse gastric cancer patients also revealed an overexpression of PGK1 in patients with development of peritoneal carcinomatosis. Therefore, PGK1 may be a crucial enzyme in peritoneal dissemination. Together these findings suggest that the enhanced expression of PGK1 and its signaling targets CXCR4 and β‐catenin in gastric cancer cells promote peritoneal carcinomatosis. Thus, PGK1 may serve as prognostic marker and/or be a potential therapeutic target to prevent dissemination of gastric carcinoma cells into the peritoneum.
The combined assessment of Skp2 and p27 identifies aggressive breast cancer. In long-term follow-up, high Skp2 and low p27 indicate an unfavorable course. Beyond the prognostic importance of the Skp2/p27 index, it could serve as a predictive marker for new molecular targeted therapies aiming at Skp2.
BACKGROUND Soft‐tissue sarcomas (STSs) are a heterogeneous group of malignant tumors that can be difficult to treat. This is particularly true after incomplete or unplanned excisions and especially for patients with American Joint Committee on Cancer stage III tumors, who are at high risk for relapse. Numerous studies have shown that an inadequate sarcoma excision is associated with a worse prognosis. However, other reports have suggested an improved prognosis for patients with an initial unplanned excision and subsequent re‐excision in comparison with patients who undergo planned primary surgery. The purpose of this study was to determine the impact of an unplanned excision on treatment and subsequent oncologic and functional outcomes for patients with stage III extremity STS. METHODS From the prospectively collected database at a tertiary‐referral sarcoma center, all patients with stage III STS of the extremities treated between 1989 and 2010 were identified. Patient records were reviewed to identify patient demographics, tumor details, treatments, complications, and functional and oncologic outcomes. RESULTS Five hundred patients with stage III STSs of the extremities were identified, and 94 of these patients (18.8%) were referred after inadequate excisions had been performed elsewhere. All 94 patients with unplanned excisions underwent re‐excision in an attempt to achieve clear margins, and 83% of these patients had residual tumor in the re‐excision specimen. In the re‐excision group, the rates of plastic reconstruction (eg, skin grafts and rotational or free flaps) and amputation were significantly higher in comparison with the rates for patients who underwent a primary planned resection (P = .023 and P = .03, respectively). The rates of local recurrence, metastasis‐free survival, and overall survival were not significantly different between the 2 groups, nor were the functional outcomes. CONCLUSIONS Unplanned excision of stage III STS leads to an unfavorable clinical course and necessitates more extensive surgery. As a result of aggressive re‐excision and multidisciplinary treatment, a negative effect on oncologic outcomes cannot be confirmed.
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