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Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature
Background:Given the large number of genes purported to be prognostic for breast cancer, it would be optimal if the genes identified are not confounded by the continuously changing systemic therapies. The aim of this study was to discover and validate a breast cancer prognostic expression signature for distant metastasis in untreated, early stage, lymph node-negative (N-) estrogen receptor-positive (ER+) patients with extensive follow-up times.Methods:197 genes previously associated with metastasis and ER status were profiled from 142 untreated breast cancer subjects. A "metastasis score" (MS) representing fourteen differentially expressed genes was developed and evaluated for its association with distant-metastasis-free survival (DMFS). Categorical risk classification was established from the continuous MS and further evaluated on an independent set of 279 untreated subjects. A third set of 45 subjects was tested to determine the prognostic performance of the MS in tamoxifen-treated women.Results:A 14-gene signature was found to be significantly associated (p < 0.05) with distant metastasis in a training set and subsequently in an independent validation set. In the validation set, the hazard ratios (HR) of the high risk compared to low risk groups were 4.02 (95% CI 1.91-8.44) for the endpoint of DMFS and 1.97 (95% CI 1.28 to 3.04) for overall survival after adjustment for age, tumor size and grade. The low and high MS risk groups had 10-year estimates (95% CI) of 96% (90-99%) and 72% (64-78%) respectively, for DMFS and 91% (84-95%) and 68% (61-75%), respectively for overall survival. Performance characteristics of the signature in the two sets were similar. Ki-67 labeling index (LI) was predictive for recurrent disease in the training set, but lost significance after adjustment for the expression signature. In a study of tamoxifen-treated patients, the HR for DMFS in high compared to low risk groups was 3.61 (95% CI 0.86-15.14). Conclusions:The 14-gene signature is significantly associated with risk of distant metastasis. The signature has a predominance of proliferation genes which have prognostic significance above that of Ki-67 LI and may aid in prioritizing future mechanistic studies and therapeutic interventions.
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Leptin receptor Gln223Arg polymorphism and breast cancer risk in Nigerian women: A case control study
Background:Leptin, a 16 kDa polypeptide hormone, implicated in various physiological processes, exerts its action through the leptin receptor, a member of the class I cytokine receptor family. Both leptin and leptin receptor have recently been implicated in processes leading to breast cancer initiation and progression in animal models and humans. An A to G transition mutation in codon 223 in exon 6 of the leptin receptor gene, resulting in glutamine to arginine substitution (Gln223Arg), lies within the first of two putative leptin-binding regions and may be associated with impaired signaling capacity of the leptin receptor. This study was designed to assess the role of this polymorphism in breast cancer susceptibility in Nigerian women.Methods:We utilized a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay to evaluate the association between the Gln223RArg polymorphism of the leptin receptor gene and breast risk in Nigeria in a case control study involving 209 women with breast cancer and 209 controls without the disease. Study participants were recruited from surgical outpatient clinics and surgical wards of four University Teaching Hospitals located in Midwestern and southeastern Nigeria between September 2002 and April 2004. Results:Premenopausal women carrying at least one LEPR 223Arg allele were at a modestly increased risk of breast cancer after adjusting for confounders (OR=1.8, 95% confidence interval [CI] 1.0-3.2, p=0.07). There was no association with postmenopausal breast cancer risk (OR=0.9, 95% CI 0.4-1.8, p=0.68). Conclusions:Our results suggest that the LEPR Gln223Arg polymorphism in the extracellular domain of the LEPR receptor gene is associated with a modestly increased risk of premenopausal breast cancer in Nigerian women.
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Activation of MEK1 or MEK2 isoform is sufficient to fully transform intestinal epithelial cells and induce the formation of metastatic tumors
Background:The Ras-dependent ERK1/2 MAP kinase signaling pathway plays a central role in cell proliferation control and is frequently activated in human colorectal cancer. Small-molecule inhibitors of MEK1/MEK2 are therefore viewed as attractive drug candidates for the targeted therapy of this malignancy. However, the exact contribution of MEK1 and MEK2 to the pathogenesis of colorectal cancer remains to be established. Methods:Wild type and constitutively active forms of MEK1 and MEK2 were ectopically expressed by retroviral gene transfer in the normal intestinal epithelial cell line IEC-6. We studied the impact of MEK1 and MEK2 activation on cellular morphology, cell proliferation, survival, migration, invasiveness, and tumorigenesis in mice. RNA interference was used to test the requirement for MEK1 and MEK2 function in maintaining the proliferation of human colorectal cancer cells.Results:We found that expression of activated MEK1 or MEK2 is sufficient to morphologically transform intestinal epithelial cells, dysregulate cell proliferation and induce the formation of high-grade adenocarcinomas after orthotopic transplantation in mice. A large proportion of these intestinal tumors metastasize to the liver and lung. Mechanistically, activation of MEK1 or MEK2 up-regulates the expression of matrix metalloproteinases, promotes invasiveness and protects cells from undergoing anoikis. Importantly, we show that silencing of MEK2 expression completely suppresses the proliferation of human colon carcinoma cell lines, whereas inactivation of MEK1 has a much weaker effect. Conclusions:MEK1 and MEK2 isoforms have similar transforming properties and are able to induce the formation of metastatic intestinal tumors in mice. Our results suggest that MEK2 plays a more important role than MEK1 in sustaining the proliferation of human colorectal cancer cells.
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Cancercompass: top stories News
NEW YORK, NY -- Propelled by advances in molecular biology, the treatment of colorectal cancer is on the verge of dramatic change and a promising future as innovative vaccines will replace chemotherapy. According to a new report from Kalorama Information, "Cancer Vaccines: Market Forecasts, New Developments and Pipeline Analysis," this market, lead by OncoVAX, is poised for unprecedented growth, creating countless opportunities for market participants. More than 1.2 million cases of colon cancer are diagnosed worldwide each year with more than 529,000 deaths, which displays a considerable medical need. In the United States colorectal cancer is the second most common cause of cancer, accounting for approximately 50,000 d...
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OncoVAX, Other Vaccines Provide Hope For Colorectal Cancer Treatment, Prevention
CORONA, Calif. -- Watson Pharmaceuticals, Inc., a leading specialty pharmaceutical company, today announced that its New Drug Application (NDA) for a 6-month formulation of TRELSTAR(R) (triptorelin pamoate), a luteinizing hormone releasing hormone (LHRH) agonist, has been accepted for filing by the U.S. Food and Drug Administration (FDA). Watson is seeking marketing approval of this TRELSTAR(R) formulation for the palliative treatment of advanced prostate cancer. Watson anticipates that FDA will take action on its application in the third quarter 2009. The sustained-release formulation of TRELSTAR(R) is designed to suppress the production of testosterone in men with advanced prostate cancer over 6 months. Prostate can...
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Watson Announces The NDA For A 6-Month Formulation Of Trelstar Accepted For Filing By FDA For The Treatment Of Advanced Prostate Cancer
The human papillomavirus (HPV) allows infected cervical and head and neck cancer cells to maintain internal molecular conditions that make the cancers resistant to therapy and more likely to grow and spread, resulting in a poor prognosis for patients, researchers with UCLA's Jonsson Cancer Center found. Virtually all human cancers experience a state called intratumoral hypoxia, or a low amount of oxygen within the tumor. In the UCLA study, researchers showed that the HPV-positive cancers adapted to and took advantage of the hypoxic environment by expressing a protein that activates a cell signaling pathway that helps the cancers survive, grow and spread. The study is published in the Nov. 4, 2008 issue of the journal Cancer Cell. Th...
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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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