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The expression of the ubiquitin ligase SIAH2 (seven in absentia homolog 2) is mediated through gene copy number in breast cancer and is associated with a basal-like phenotype and p53 expression
Peter Chan, Andreas M?ller, Mira CP Liu, Jaclyn E Sceneay, Christina SF Wong, Nic Waddell, Katie T Huang, Alexander Dobrovic, Ewan KA Millar, Sandra A O'Toole, Catriona M McNeil, Robert L Sutherland, David D Bowtell, Stephen B Fox
Breast Cancer Research , 2011, DOI: 10.1186/bcr2828
Abstract: Immunohistochemical evaluation of SIAH2protein expression was conducted in normal breast tissues and in tissue microarrays comprising ductal carcinoma in situ (DCIS) and a cohort of invasive breast carcinomas. Correlation analysis was performed between SIAH2 and clinicopathological variables and intrinsic breast cancer subgroups and validated in a cohort of 293 invasive ductal carcinomas. Promoter methylation, gene copy number and mRNA expression of SIAH2 were determined in a panel of basal-like tumors and cell lines.There was a significant increase in nuclear SIAH2 expression from normal breast tissues through to DCIS and progression to invasive cancers. A significant inverse correlation was apparent between SIAH2 and estrogen receptor and progesterone receptor and a positive association with tumor grade, HER2, p53 and an intrinsic basal-like subtype. Logistic regression analysis confirmed the significant positive association between SIAH2 expression and the basal-like phenotype. No SIAH2 promoter methylation was identified, yet there was a significant correlation between SIAH2 mRNA and gene copy number. SIAH2-positive tumors were associated with a shorter relapse-free survival in univariate but not multivariate analysis.SIAH2 expression is upregulated in basal-like breast cancers via copy number changes and/or transcriptional activation by p53 and is likely to be partly responsible for the enhanced hypoxic drive through abrogation of the prolyl hydroxylases.Hypoxia in breast cancer has profound effects on tumor biology that are reflected in a poor prognosis and resistance to both chemotherapy and radiotherapy in patients [1]. Hypoxia-inducible factor (HIF)-1 is critical to the hypoxic response, being a transcription factor that, through binding to hypoxia response elements in the promoters of genes, results in expression of proteins involved in angiogenesis (vascular endothelial growth factor (VEGF)), glucose metabolism (glucose transporter 1), metastasis (chemoki
Amplified Loci on Chromosomes 8 and 17 Predict Early Relapse in ER-Positive Breast Cancers  [PDF]
Erhan Bilal, Kristen Vassallo, Deborah Toppmeyer, Nicola Barnard, Inga H. Rye, Vanessa Almendro, Hege Russnes, Anne-Lise B?rresen-Dale, Arnold J. Levine, Gyan Bhanot, Shridar Ganesan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038575
Abstract: Adjuvant hormonal therapy is administered to all early stage ER+ breast cancers, and has led to significantly improved survival. Unfortunately, a subset of ER+ breast cancers suffer early relapse despite hormonal therapy. To identify molecular markers associated with early relapse in ER+ breast cancer, an outlier analysis method was applied to a published gene expression dataset of 268 ER+ early-stage breast cancers treated with tamoxifen alone. Increased expression of sets of genes that clustered in chromosomal locations consistent with the presence of amplicons at 8q24.3, 8p11.2, 17q12 (HER2 locus) and 17q21.33-q25.1 were each found to be independent markers for early disease recurrence. Distant metastasis free survival (DMFS) after 10 years for cases with any amplicon (DMFS = 56.1%, 95% CI = 48.3–63.9%) was significantly lower (P = 0.0016) than cases without any of the amplicons (DMFS = 87%, 95% CI = 76.3% –97.7%). The association between presence of chromosomal amplifications in these regions and poor outcome in ER+ breast cancers was independent of histologic grade and was confirmed in independent clinical datasets. A separate validation using a FISH-based assay to detect the amplicons at 8q24.3, 8p11.2, and 17q21.33-q25.1 in a set of 36 early stage ER+/HER2- breast cancers treated with tamoxifen suggests that the presence of these amplicons are indeed predictive of early recurrence. We conclude that these amplicons may serve as prognostic markers of early relapse in ER+ breast cancer, and may identify novel therapeutic targets for poor prognosis ER+ breast cancers.
Dormancy in breast cancer  [cached]
Banys M,Hartkopf AD,Krawczyk N,Kaiser T
Breast Cancer: Targets and Therapy , 2012,
Abstract: Malgorzata Banys,1,2 Andreas D Hartkopf,1 Natalia Krawczyk,1 Tatjana Kaiser,1 Franziska Meier-Stiegen,1 Tanja Fehm,1 Hans Neubauer11Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany; 2Department of Obstetrics and Gynecology, Marienkrankenhaus Hamburg, Hamburg, GermanyAbstract: Tumor dormancy describes a prolonged quiescent state in which tumor cells are present, but disease progression is not yet clinically apparent. Breast cancer is especially known for long asymptomatic periods, up to 25 years, with no evidence of the disease, followed by a relapse. Factors that determine the cell's decision to enter a dormant state and that control its duration remain unclear. In recent years, considerable progress has been made in understanding how tumor cells circulating in the blood interact and extravasate into secondary sites and which factors might determine whether these cells survive, remain dormant, or become macrometastases. The mechanisms of tumor cell dormancy are still not clear. Two different hypotheses are currently discussed: tumor cells persist either by completely withdrawing from the cell cycle or by continuing to proliferate at a slow rate that is counterbalanced by cell death. Because dormant disseminated tumor cells may be the founders of metastasis, one hypothesis is that dormant tumor cells, or at least a fraction of them, share stem cell-like characteristics that may be responsible for their long half-lives and their suggested resistance to standard chemotherapy. Therefore, knowledge of the biology of tumor cell dormancy may be the basis from which to develop innovative targeted therapies to control or eliminate this tumor cell fraction. In this review, we discuss biological mechanisms and clinical implications of tumor dormancy in breast cancer patients.Keywords: tumor dormancy, disseminated tumor cell, circulating tumor cell, targeted therapy
Breast cancer stem cells: tools and models to rely on
Emmanuelle Charafe-Jauffret, Christophe Ginestier, Daniel Birnbaum
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-202
Abstract: Understanding the role of CSCs during carcinogenesis, from tumor initiation to metastasis formation, has become a major focus in stem cell biology and in cancer research. Considerable efforts are directed towards developing clinical applications of the CSC concept. However, it is crucial to functionally validate each marker and model utilized to isolate and characterized CSC. In this review, we give an overview of the tools available to study breast CSCs and describe their implications to improve breast cancer treatment. The cancer stem cell (CSC) model holds that tumors are organized in a cellular hierarchy in which CSCs are the only cells with unlimited proliferation potential and with the capability of driving tumor growth and progression. According to this model, cancers originate from the malignant transformation of an adult stem cell or progenitor through the disregulation of the normally tightly regulated self-renewal program. This leads to clonal expansion of stem/progenitor cells that undergo further genetic or epigenetic alterations to become fully transformed. As a consequence of this, tumors contain a cellular component of CSCs which retain the key stem cell properties that initiate and drive carcinogenesis.A major goal of both researchers and oncologists is to understand how many and which tumor cells must be eliminated for a given treatment to succeed. Eliminating cancer cells that have limited proliferation potential, while sparing cancer stem cells that have unlimited proliferation potential will eventually result in relapse or recurrence. This hypothesis has been recently validated by different studies that described CSCs from various tissues as a cell population resistant to current anticancer therapies, antimitotic agents and radiation [1-6].Some years ago, a subset of cells from a neuroblastoma cell line identified upon their capacity to exclude vital dye as a Side Population (SP cells) showed the ability to resist chemotherapy. Although SP and n
Solitary adrenal metastasis from invasive ductal breast cancer: an uncommon finding
Xiao-Jiao Liu, Peng Shen, Xin-Feng Wang, Ke Sun, Fei-Fei Sun
World Journal of Surgical Oncology , 2010, DOI: 10.1186/1477-7819-8-7
Abstract: A 64-year-old woman was found a left adrenal mass on a follow- up visit two years after taking a right modified radical mastectomy for the breast cancer. She was subsequently given a left adrenalectomy. Postoperative histopathology findings were compatible with invasive ductal carcinoma (IDC) of the breast. Due to the patient's refusal, no further treatments were offered after the adrenalectomy. The patient now is still alive and has no sign of relapse. Survival time after taking the right modified radical mastectomy and the left adrenalectomy is more than five years and three years, respectively.This is the first case of a patient with solitary, metachronous adrenal metastasis from IDC of the breast to be reported. For patients in this condition, complete removal of metastasized organ may translate into survival benefit.Invasive ductal carcinoma (IDC) is the most common type of the breast cancer, which has been reported to constitute approximately 70-85% of all invasive breast carcinomas[1]. Usually, IDC can metastasize to the lungs, liver, bones and brain, but rarely to the adrenal glands[2,3]. In a study of metastatic patterns of breast cancer, Borst MJ[2] reported that in a group of the 2246 patients with IDC, none of them had shown adrenal metastasis. In fact, adrenal metastasis of breast cancer is generally associated with infiltrating lobular carcinomas (ILC) and often accompanied by synchronous multiorgan metastases[3]. A metachronous, isolated adrenal metastasis from ILC is rare, which is even rarer when it derives from IDC of the breast. So far there has been only one case of isolated adrenal metastasis arising from ILC of the breast documented [4], but the IDC with solitary adrenal metastasis has never been reported in the literature.Due to the rarity of solitary adrenal metastasis from breast cancer, the optimal treatment is still unclear. Generally, distant visceral metastasis is an upset aspect for cancer patient, palliative chemotherapy would be recom
Dormancy in breast cancer
Banys M, Hartkopf AD, Krawczyk N, Kaiser T, Meier-Stiegen F, Fehm T, Neubauer H
Breast Cancer: Targets and Therapy , 2012, DOI: http://dx.doi.org/10.2147/BCTT.S26431
Abstract: rmancy in breast cancer Review (1751) Total Article Views Authors: Banys M, Hartkopf AD, Krawczyk N, Kaiser T, Meier-Stiegen F, Fehm T, Neubauer H Published Date December 2012 Volume 2012:4 Pages 183 - 191 DOI: http://dx.doi.org/10.2147/BCTT.S26431 Received: 07 June 2012 Accepted: 11 July 2012 Published: 05 December 2012 Malgorzata Banys,1,2 Andreas D Hartkopf,1 Natalia Krawczyk,1 Tatjana Kaiser,1 Franziska Meier-Stiegen,1 Tanja Fehm,1 Hans Neubauer1 1Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany; 2Department of Obstetrics and Gynecology, Marienkrankenhaus Hamburg, Hamburg, Germany Abstract: Tumor dormancy describes a prolonged quiescent state in which tumor cells are present, but disease progression is not yet clinically apparent. Breast cancer is especially known for long asymptomatic periods, up to 25 years, with no evidence of the disease, followed by a relapse. Factors that determine the cell's decision to enter a dormant state and that control its duration remain unclear. In recent years, considerable progress has been made in understanding how tumor cells circulating in the blood interact and extravasate into secondary sites and which factors might determine whether these cells survive, remain dormant, or become macrometastases. The mechanisms of tumor cell dormancy are still not clear. Two different hypotheses are currently discussed: tumor cells persist either by completely withdrawing from the cell cycle or by continuing to proliferate at a slow rate that is counterbalanced by cell death. Because dormant disseminated tumor cells may be the founders of metastasis, one hypothesis is that dormant tumor cells, or at least a fraction of them, share stem cell-like characteristics that may be responsible for their long half-lives and their suggested resistance to standard chemotherapy. Therefore, knowledge of the biology of tumor cell dormancy may be the basis from which to develop innovative targeted therapies to control or eliminate this tumor cell fraction. In this review, we discuss biological mechanisms and clinical implications of tumor dormancy in breast cancer patients.
Rare localisation of breast cancer metastasis to thyroid gland  [PDF]
Kolarevi? Daniela,Toma?evi? Zorica,Markovi? Ivan,?egarac Milan
Vojnosanitetski Pregled , 2012, DOI: 10.2298/vsp1212106k
Abstract: Introduction. Metastases to the thyroid gland are very rare. They are usually seen in malignant melanoma, kidney, breast cancer and lung cancer. Case report. We presented a 54- years-old female patient with breast cancer diagnosed in 2002. The adequate surgical procedure was done and the tumor and axillary lymph nodes were removed. The patient also received adjuvant postoperative chemotherapy. After seven years of a disease free period, the first relapse of the disease was detected as thyroid gland tumor with axillary lymphadenopathy. The patient had a good response to systemic treatment so the surgical removal of thyroid gland and enlarged lymph nodes was performed. Histopathological analysis confirmed metastasis with breast cancer origin. Radical mastectomy was also preformed. Second relapse of the disease was detected 10 months later, while the patient was on hormonal therapy. It was manifested as the appearance of bone and skin metastases, pleural effusion and lymphadenopathy. Conclusion. This case report emphasized the importance of detailed examination of any new onset of thyroid swelling in a patient with previous history of malignancy.
Five-Year Follow-Up of Patients with Early Stage Breast Cancer After a Randomized Study Comparing Additional Treatment with Viscum Album (L.) Extract to Chemotherapy Alone
Wilfried Tr ger, Zdravko drale, Nikola Stankovic and Miodrag Matija evic
Breast Cancer: Basic and Clinical Research , 2012, DOI: 10.4137/BCBCR.S10558
Abstract: Additional therapy with extracts of Viscum album [L.] (VaL) increases the quality of life of patients suffering from early stage breast cancer during chemotherapy. In the current study patients received chemotherapy, consisting of six cycles of cyclophosphamide, anthracycline, and 5-Fluoro-Uracil (CAF). Two groups also received one of two VaL extracts differing in their preparation as subcutaneous injection three times per week. A control group received CAF with no additional therapy. Six of 28 patients in one of the VaL groups and eight of 29 patients in the control group developed relapse or metastasis within 5 years. Subgroup analysis for hormone- and radiotherapy also showed no difference between groups. Additional VaL therapy during chemotherapy of early stage breast cancer patients appears not to influence the frequency of relapse or metastasis within 5 years.
Late solitary testicular metastasis from rectal cancer  [cached]
Venkitaraman Ramachandran,George Mathew,Weerasooriya Suranga,Selva-Nayagam Sid
Journal of Cancer Research and Therapeutics , 2010,
Abstract: Isolated testicular metastasis from rectal cancer is rare. We describe the case of a patient who presented with a locally advanced rectal malignancy and underwent multimodality treatment with low anterior resection, postoperative radiotherapy and adjuvant chemotherapy. He developed a painless testicular nodule while on follow-up, five years after the diagnosis of primary rectal cancer. Histopathology and immunohistochemistry of orchidectomy specimen were compatible with a metastatic adenocarcinoma of rectal origin. We hypothesize that this phenomenon of isolated relapse in a sanctuary site could be due to the altered biology and pattern of metastasis as a result of effective adjuvant systemic chemotherapy. Treatment of late isolated relapse in the testis needs to be ascertained.
Breast cancer surface receptors predict risk for developing brain metastasis and subsequent prognosis
Jai Grewal, Santosh Kesari
Breast Cancer Research , 2008, DOI: 10.1186/bcr1868
Abstract: The retrospective analysis presented by Nam and coworkers [1] is consistent with prior data suggesting increased risk for brain metastases and shortened survival in patients with brain metastases when there is a lack of surface hormone receptors (estrogen receptor [ER]-negative/progesterone receptor [PR]-negative status). This study goes one step further and attempts to correlate the outcomes of brain metastasis with intrinsic breast cancer subtypes, using the receptor combinations as a surrogate marker for the subtypes defined by gene expression microarrays. There appears to be a higher proportion of human epidermal growth factor receptor (HER)2-positive/ER-negative and triple-negative disease among patients with brain metastases. HER2-positive status did not appear to increase the risk for brain metastasis, as described in other studies [2,3]. There are conflicting data in the literature on the significance of HER2 with regard to brain metastases in breast cancer, and several unanswered questions remain. Does HER2 positivity affect risk for brain metastasis? Does HER2 positivity affect survival among breast cancer patients with brain metastases? Finally, do these correlations with parenchymal brain metastases extend to leptomeningeal disease (LMD)?Regarding the first question, there are conflicting findings in the literature on the correlation between HER2 status and the risk for brain metastasis. HER2-positive breast cancer has been associated with increased risk for brain metastases in some studies [2,3], but others found no significant association [1,4]. In considering the possibility that HER2-positive status may increase the risk for brain metastasis, several confounding issues must be considered in the trastuzumab era. It has been suggested that trastuzumab itself may be related to the increased risk for brain metastasis [5]. However, trastuzumab has also resulted in improved survival in HER2-positive metastatic breast cancer. Because brain metastasis typica
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