Background:ER+/HER2− breast cancers have a proclivity for late recurrence. A personalised estimate of relapse risk after 5 years of endocrine treatment can improve patient selection for extended hormonal therapy.Methods:A total of 1702 postmenopausal ER+/HER2− breast cancer patients from two adjuvant phase III trials (ABCSG6, ABCSG8) treated with 5 years of endocrine therapy participated in this study. The multigene test EndoPredict (EP) and the EPclin score (which combines EP with tumour size and nodal status) were predefined in independent training cohorts. All patients were retrospectively assigned to risk categories based on gene expression and on clinical parameters. The primary end point was distant metastasis (DM). Kaplan–Meier method and Cox regression analysis were used in an early (0–5 years) and late time interval (>5 years post diagnosis).Results:EP is a significant, independent, prognostic parameter in the early and late time interval. The expression levels of proliferative and ER signalling genes contribute differentially to the underlying biology of early and late DM. The EPclin stratified 64% of patients at risk after 5 years into a low-risk subgroup with an absolute 1.8% of late DM at 10 years of follow-up.Conclusion:The EP test provides additional prognostic information for the identification of early and late DM beyond what can be achieved by combining the commonly used clinical parameters. The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of endocrine therapy. The side effects of extended therapy should be weighed against this projected outcome.

In the majority of human tumors, expression of the c-MYC oncogene becomes constitutive. Here, we report that c-MYC directly regulates the expression of AP4 via CACGTG motifs in the first intron of the AP4 gene. Induction of AP4 was required for c-MYCmediated cell cycle reentry of anti-estrogen arrested breast cancer cells and mitogen-mediated repression of the CDK inhibitor p21. AP4 directly repressed p21 by occupying four CAGCTG motifs in the p21 promoter via its basic region. AP4 levels declined after DNA damage, and ectopic AP4 interfered with p53-mediated cell cycle arrest and sensitized cells to apoptosis induced by DNA damaging agents. AP4 expression blocked induction of p21 by TGF-␤ in human keratinocytes and interfered with up-regulation of p21 and cell cycle arrest during monoblast differentiation. Notably, AP4 is specifically expressed in colonic progenitor and colorectal carcinoma cells. In conclusion, our results indicate that c-MYC employs AP4 to maintain cells in a proliferative, progenitor-like state.colorectal cancer ͉ DNA damage ͉ p53 ͉ progenitor cells ͉ TGF-beta

Deregulated TGF-b signaling in pancreatic cancer promotes tumor growth, invasion, metastasis, and a potent immunosuppressive network. A strategy for disrupting this tumor-promoting pathway is silencing TGF-b by siRNA. By introducing a triphosphate group at the 5 0 end of siRNA (ppp-siRNA), gene silencing can be combined with immune activation via the cytosolic helicase retinoic acid-inducible gene I (RIG-I), a ubiquitously expressed receptor recognizing viral RNA. We validated RIG-I as a therapeutic target by showing that activation of RIG-I in pancreatic carcinoma cells induced IRF-3 phosphorylation, production of type I IFN, the chemokine CXCL10, as well as caspase-9-mediated tumor cell apoptosis. Next, we generated a bifunctional ppp-siRNA that combines RIG-

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Metastatic invasion is the major cause of cancer-related deaths. In this study, we introduce two-pore channels (TPC), a recently described class of NAADP- and PI(3,5)P2-sensitive Ca-permeable cation channels in the endolysosomal system of cells, as candidate targets for the treatment of invasive cancers. Inhibition of the channel abrogated migration of metastatic cancer cells Silencing or pharmacologic inhibition of the two-pore channel TPC2 reduced lung metastasis of mammary mouse cancer cells. Disrupting TPC function halted trafficking of β1-integrin, leading to its accumulation in EEA1-positive early endosomes. As a consequence, invasive cancer cells were no longer able to form leading edges, which are required for adequate migration. Our findings link TPC to cancer cell migration and provide a preclinical proof of concept for their candidacy as targets to treat metastatic cancers..

BackgroundIn early estrogen receptor (ER)-positive/HER2-negative breast cancer, the decision to administer chemotherapy is largely based on prognostic criteria. The combined molecular/clinical EndoPredict test (EPclin) has been validated to accurately assess prognosis in this population. In this study, the clinical relevance of EPclin in relation to well-established clinical guidelines is assessed.Patients and methodsWe assigned risk groups to 1702 ER-positive/HER2-negative postmenopausal women from two large phase III trials treated only with endocrine therapy. Prognosis was assigned according to National Comprehensive Cancer Center Network-, German S3-, St Gallen guidelines and the EPclin. Prognostic groups were compared using the Kaplan–Meier survival analysis.ResultsAfter 10 years, absolute risk reductions (ARR) between the high- and low-risk groups ranged from 6.9% to 11.2% if assigned according to guidelines. It was at 18.7% for EPclin. EPclin reassigned 58%–61% of women classified as high-/intermediate-risk (according to clinical guidelines) to low risk. Women reclassified to low risk showed a 5% rate of distant metastasis at 10 years.ConclusionThe EPclin score is able to predict favorable prognosis in a majority of patients that clinical guidelines would assign to intermediate or high risk. EPclin may reduce the indications for chemotherapy in ER-positive postmenopausal women with a limited number of clinical risk factors.

For classification of breast cancer (BC), tumor-node-metastasis (TNM) staging has been considered state of the art for more than 50 years. The T category is well defined, and in multicentric and multifocal tumors, tumor size is assessed by the largest tumor focus. The aim of this study was to compare multicentric/multifocal tumor spread in breast cancer with unifocal disease and to evaluate the diagnostic relevance of multifocality. A retrospective analysis was performed on survival related events in a series of 5,691 breast cancer patients between 1963 and 2007. By matched-pair analysis, patients were entered into two comparable groups of 288 patients after categorizing them as having multifocal/multicentric or unifocal breast cancers. Matching criteria were tumor size, grading, and hormone receptor status, which were equally distributed between both groups (P = 1.000 each). Disease free survival and the occurrence of relapse or of metastatic disease were evaluated. Cox's regression analysis was used for multivariate analysis. In the unifocal group, the mean breast cancer-specific survival time was 221.6 months as opposed to 203.3 months in the multicentric/multifocal group (P < 0.001, log-rank test). The occurrence of local relapse and distant metastasis was significantly increased in the multifocal group in comparison to the unifocal equivalent group (P < 0.001 and P < 0.003, respectively). Cox regression analysis for multivariate analyses demonstrated focality and centricity to be highly significant predictors for reduced overall survival (P = 0.016), local relapse (P = 0.001) and distant metastasis (P = 0.038). Tumor size, histopathological grading, hormone receptor status, and staging of lymph nodes are well-established prognostic parameters. Additionally, the number of foci should be considered as an independent prognostic parameter, which is currently not reflected in the TNM classification. We conclude that multicentric/multifocal BC is an independent BC risk factor and should be included in the risk assessment by re-evaluating the current TNM classification of the UICC.

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