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TDAG51 is an ERK signaling target that opposes ERK-mediated HME16C mammary epithelial cell transformation
IntroductionSignaling downstream of Ras is mediated by three major pathways, Raf/ERK, phosphatidylinositol 3 kinase (PI3K), and Ral guanine nucleotide exchange factor (RalGEF). Ras signal transduction pathways play an important role in breast cancer progression, as evidenced by the frequent over-expression of the Ras-activating epidermal growth factor receptors EGFR and ErbB2. Here we investigated which signal transduction pathways downstream of Ras contribute to EGFR-dependent transformation of telomerase-immortalized mammary epithelial cells HME16C. Furthermore, we examined whether a highly transcriptionally regulated ERK pathway target, PHLDA1 (TDAG51), suggested to be a tumor suppressor in breast cancer and melanoma, might modulate the transformation process. Methods: Cellular transformation of human mammary epithelial cells by downstream Ras signal transduction pathways was examined using anchorage-independent growth assays in the presence and absence of EGFR inhibition. TDAG51 protein expression was down-regulated by interfering small hairpin RNA (shRNA), and the effects on cell proliferation and death were examined in Ras pathway-transformed breast epithelial cells. Results: Activation of both the ERK and PI3K signaling pathways was sufficient to induce cellular transformation, which was accompanied by up-regulation of EGFR ligands, suggesting autocrine EGFR stimulation during the transformation process. Only activation of the ERK pathway was sufficient to transform cells in the presence of EGFR inhibition and was sufficient for tumorigenesis in xenografts. Up-regulation of the PHLDA1 gene product, TDAG51, was found to correlate with persistent ERK activation and anchorage-independent growth in the absence or presence of EGFR inhibition. Knockdown of this putative breast cancer tumor-suppressor gene resulted in increased ERK pathway activation and enhanced matrix-detached cellular proliferation of Ras/Raf transformed cells. Conclusions: Our results suggest that multiple Ras signal transduction pathways contribute to mammary epithelial cell transformation, but that the ERK signaling pathway may be a crucial component downstream of EGFR activation during tumorigenesis. Furthermore, persistent activation of ERK signaling up-regulates TDAG51. This event serves as a negative regulator of both Erk activation as well as matrix-detached cellular proliferation and suggests that TDAG51 opposes ERK-mediated transformation in breast epithelial cells.
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Clinical implications of thymidylate synthetase, dihydropyrimidine dehydrogenase and orotate phosphoribosyl transferase activity levels in colorectal carcinoma following radical resection and administration of adjuvant 5-FU chemotherapy
Background:A number of studies have investigated whether the activity levels of enzymes involved in 5-fluorouracil (5-FU) metabolism are prognostic factors for survival in patients with colorectal carcinoma. Most reports have examined thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) in unresectable or metastatic cases, therefore it is unclear whether the activity of these enzymes is of prognostic value in colorectal cancer patients treated with radical resection and adjuvant chemotherapy with 5-FU.Methods:This study examined fresh frozen specimens of colorectal carcinoma from 40 patients who had undergone curative operation and were orally administered adjuvant tegafur/uracil (UFT) chemotherapy. TS, DPD and orotate phosphoribosyl transferase (OPRT) activities were assayed in cancer tissue and adjacent normal tissue and their association with clinicopathological variables was investigated. In addition, the relationships between TS, DPD and OPRT activities and patient survival were examined to determine whether any of these enzymes could be useful prognostic factors.Results:While there was no clear relationship between pathological findings and TS or DPD activity, OPRT activity was significantly lower in tumors with lymph node metastasis than in tumors lacking lymph node metastasis. Postoperative survival was significantly better in the groups with low TS activity and/or high OPRT activity. Conclusions:TS and OPRT activity levels in tumor tissue may be important prognostic factors for survival in Dukes' B and C colorectal carcinoma with radical resection and adjuvant chemotherapy with UFT.
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Metastatic susceptibility locus, an 8p hot-spot for tumour progression disrupted in colorectal liver metastases: 13 candidate genes examined at the DNA, mRNA and protein level.
Background:Mortality from colorectal cancer is mainly due to metastatic liver disease. Improved understanding of the molecular events underlying metastasis is crucial for the development of new methods for early detection and treatment of colorectal cancer. Loss of chromosome 8p is frequently seen in colorectal cancer and implicated in later stage disease and metastasis, although a single metastasis suppressor gene has yet to be identified. We therefore examined 8p for genes involved in colorectal cancer progression.Methods:Loss of heterozygosity analyses were used to map genetic loss in colorectal liver metastases. Candidate genes in the region of loss were investigated in clinical samples from 44 patients, including 6 with matched colon normal, colon tumour and liver metastasis. We investigated gene disruption at the level of DNA, mRNA and protein using a combination of mutation, semi-quantitative real-time PCR, western blotting and immunohistochemical analyses. Results:We mapped a 2Mb region of 8p21-22 with loss of heterozygosity in 73% of samples; 8/11 liver metastasis samples had loss which was not present in the corresponding matched primary colon tumour. 13 candidate genes were identified for further analysis. Both up and down-regulation of 8p21-22 gene expression was associated with metastasis. ADAMDEC1 mRNA and protein expression decreased during both tumourigenesis and tumour progression. Increased STC1 and LOXL2 mRNA expression occurred during tumourigenesis. Liver metastases with low DcR1/TNFRSF10C mRNA expression were more likely to present with extrahepatic metastases (p=0.005). A novel germline truncating mutation of DR5/TNFRSF10B was identified, and DR4/TNFRSF10A SNP rs4872077 was associated with the development of liver metastases (p=0.02).Conclusions:Our data confirm that genes on 8p21-22 are dysregulated during colorectal cancer progression. Interestingly, however, instead of harbouring a single candidate colorectal metastasis suppressor 8p21-22 appears to be a hot-spot for tumour progression, encoding at least 13 genes with a putative role in carcinoma development. Thus, we propose that this region of 8p comprises a metastatic susceptibility locus involved in tumour progression whose disruption increases metastatic potential.
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Cancercompass: top stories News
NEW YORK -- Prostate cancer is the second leading cause of death among American males, but when caught early, prostate cancer has a 90% cure rate. According to Dr. David Samadi, Chief, Division of Robotics and Minimally Invasive Surgery, Department of Urology, at Mount Sinai Medical Center, "The key to fighting prostate cancer is not to wait until there are warning signs, because by then it may be too late." The tendency of prostate cancer to grow without causing noticeable symptoms leads doctors to recommend that men over 50 get screened every year. However, Dr. Samadi recommends that anyone with a strong family history of the disease or other risk factors get screened at age 40. Routine screening for prostate canc...
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With Prostate Cancer, Waiting For Symptoms Is Not An Option
DURHAM, N.C. -- Optimized biological treatment -- combining advanced antibody therapy plus chemotherapy -- offers a promising approach to the treatment of a cancer called follicular lymphoma, according to a report in the June issue of "The Oncologist." "The triple-therapy approach employing upfront chemotherapy combined with an optimized radioimmunotherapy and extended biologic treatment with antibodies may represent the best chance for prolonged disease-free survival and potential cure" of patients with follicular lymphoma, according to the new article by Dr. Franz Buchegger, Dr. Oliver Press, and colleagues from the Fred Hutchinson Cancer Research Center, Seattle, and University Hospital of Lausanne, Switzerland. F...
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Combining Three Cell-Killing Effects Offers Best Chance For Cure
MARLBOROUGH, Mass. -- EXACT Sciences Corporation today announced that a major gastroenterology journal has accepted for publication a multi-center, prospective study of EXACT's Version 2 technology for early colorectal cancer detection using stool-based DNA testing. The study, conducted by Steven H. Itzkowitz, M.D, Professor of Medicine, Mount Sinai School of Medicine and his collaborators, was also recently presented in abstract form at Digestive Disease Week (DDW) in San Diego, California. With respect to the earliest cancer stages, Dukes' A and B, the abstract data from DDW reported sensitivity above 85 percent on average, with specificity above 80 percent. Sensitivity in asymptomatic screening patients and symptomatic pa...
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Health News
 MRI is better than MDCT for determining if and how far breast cancer has spread into the breast ducts and should be used before patients receive breast conserving treatment, a new study shows. "Patients have a lower survival rate if their surgical margins are positive for tumor cells. A positive surgical margin is commonly the result of inadequate resection of the cancer's intraductal component," said Akiko Shimauchi, MD, at Tohoku University in Sendai, Miyagi, Japan. "Accurate preoperative diagnosis of the intraductal component allows the surgeon to achieve a cancer-free surgical margin," she said........
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MRI Best To Detect Cancer Spread Into Breast Ducts
 Using survey data from April 2003 to March 2005 for Women's Health Clinic patients without breast cancer, scientists observed that while 16% of the participants reported a maternal relative with breast cancer, only 10% reported a paternal relative. Because mothers are much more likely to develop breast cancer than fathers, participants who reported a mother with breast cancer were excluded from the study........
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Family history of breast cancer may be missed
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