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HER2 and Upar Cooperativity Contribute to Metastatic Phenotype of HER2-Positive Breast Cancer Vineesh Indira Chandran Lund University, [email protected]

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HER2 and Upar Cooperativity Contribute to Metastatic Phenotype of HER2-Positive Breast Cancer Vineesh Indira Chandran Lund University, Vn813@Uow.Edu.Au University of Wollongong Research Online Faculty of Science, Medicine and Health - Papers Faculty of Science, Medicine and Health 2015 HER2 and uPAR cooperativity contribute to metastatic phenotype of HER2-positive breast cancer Vineesh Indira Chandran Lund University, [email protected] Serenella Eppenberger-Castori Schoenbeinstrasse Thejaswini Venkatesh Nitte University Kara L. Vine University of Wollongong, [email protected] Marie Ranson University of Wollongong, [email protected] Publication Details Indira Chandran, V., Eppenberger-Castori, S., Venkatesh, T., Vine, K. Lea. & Ranson, M. (2015). HER2 and uPAR cooperativity contribute to metastatic phenotype of HER2-positive breast cancer. Oncoscience, 2 (3), 207-224. Research Online is the open access institutional repository for the University of Wollongong. For further information contact the UOW Library: [email protected] HER2 and uPAR cooperativity contribute to metastatic phenotype of HER2-positive breast cancer Abstract Human epidermal growth factor receptor type 2 (HER2)-positive breast carcinoma is highly aggressive and mostly metastatic in nature though curable/manageable in part by molecular targeted therapy. Recent evidence suggests a subtype of cells within HER2-positive breast tumors that concomitantly expresses the urokinase plasminogen activator receptor (uPAR) with inherent stem cell/mesenchymal-like properties promoting tumor cell motility and a metastatic phenotype. This HER-positive/uPAR-positive subtype may be partially responsible for the failure of HER2-targeted treatment strategies. Herein we discuss and substantiate the cumulative preclinical and clinical evidence on HER2-uPAR cooperativity in terms of gene co-amplification and/or mRNA/protein co-overexpression. We then propose a regulatory signaling model that we hypothesize to maintain upregulation and cooperativity between HER2 and uPAR in aggressive breast cancer. An improved understanding of the HER2/uPAR interaction in breast cancer will provide critical biomolecular information that may help better predict disease course and response to therapy. Disciplines Medicine and Health Sciences | Social and Behavioral Sciences Publication Details Indira Chandran, V., Eppenberger-Castori, S., Venkatesh, T., Vine, K. Lea. & Ranson, M. (2015). HER2 and uPAR cooperativity contribute to metastatic phenotype of HER2-positive breast cancer. Oncoscience, 2 (3), 207-224. This journal article is available at Research Online: http://ro.uow.edu.au/smhpapers/2806 www.impactjournals.com/oncoscience Oncoscience 2015, Vol.2, No.3 HER2 and uPAR cooperativity contribute to metastatic phenotype of HER2-positive breast cancer Vineesh Indira Chandran1, Serenella Eppenberger-Castori2, Thejaswini Venkatesh3, Kara Lea Vine4,5,6, Marie Ranson4,5,6 1 Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden. 2 Institute for Pathology, Department of Molecular Pathology, Schoenbeinstrasse, Basel, Switzerland. 3 Nitte University Centre for Science Education and Research (NUCSER), K. S. Hegde Medical Academy, Nitte University, Deralakatte, Mangalore, Karnataka, India. 4 School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia. 5 Centre for Medical & Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia. 6 Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia. Correspondence to: Vineesh Indira Chandran, email: [email protected] Keywords: HER2/ERBB2, uPAR/PLAUR, HER2-positive breast cancer, co-overexpression, co-amplification, correlation Received: January 20, 2015 Accepted: March 16, 2015 Published: March 23, 2015 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Human epidermal growth factor receptor type 2 (HER2)-positive breast carcinoma is highly aggressive and mostly metastatic in nature though curable/manageable in part by molecular targeted therapy. Recent evidence suggests a subtype of cells within HER2-positive breast tumors that concomitantly expresses the urokinase plasminogen activator receptor (uPAR) with inherent stem cell/mesenchymal-like properties promoting tumor cell motility and a metastatic phenotype. This HER-positive/ uPAR-positive subtype may be partially responsible for the failure of HER2-targeted treatment strategies. Herein we discuss and substantiate the cumulative preclinical and clinical evidence on HER2-uPAR cooperativity in terms of gene co-amplification and/or mRNA/protein co-overexpression. We then propose a regulatory signaling model that we hypothesize to maintain upregulation and cooperativity between HER2 and uPAR in aggressive breast cancer. An improved understanding of the HER2/uPAR interaction in breast cancer will provide critical biomolecular information that may help better predict disease course and response to therapy. INTRODUCTION Established BC biomarkers predicting metastatic risk include lymph-node involvement, hormone Breast cancer (BC) is a highly heterogeneous independency, loss of histopathological differentiation disease consisting of several subtypes, each classified by of primary tumor (grade), elevated proliferation, and their unique biological signature [1, 2]. Each BC subtype angiogenesis. However, these biomarkers confidently exhibits varied responses to different therapeutic regimens. predict outcome for only ~30% of patients. Of the Treatment options for metastatic disease remains limited remaining patients some will still develop metastases despite the availability of several United States Food and whilst others will not [4]. Components of the urokinase Drug Administration (FDA) approved drugs against BC plasminogen activation system, particularly urokinase [3]. In this scenario, it is imperative to explore different plasminogen activator (uPA, Gene symbol: PLAU; therapeutic models of targeting one or more tumor- located on chromosome 10q22.2), its receptor uPAR specific biomarkers that define the more aggressive breast (Gene symbol: PLAUR; located on chromosome 19q13) carcinoma subtypes efficiently for improved management and inhibitor plasminogen activator inhibitor type 1 (PAI- of the disease. 1, Gene symbol: SERPINE1; located on chromosome www.impactjournals.com/oncoscience 207 Oncoscience 7q22.1) are proven to be associated with aggressive HER2-positive BC carcinoma. The combination of uPA/PAI-1 at the protein level is a strong and independent predictor of metastasis A working model for BC molecular taxonomy in lymph-node negative BC patients and predicts response utilizing microarray-based gene expression profiling to hormone therapy [5, 6]. uPAR is expressed in malignant classifies BCs by hierarchical cluster analysis, using an cells and in the tumor stroma which translates into an intrinsic gene list, into four main molecular subtypes: aggressive tumor phenotype and poor relapse-free survival luminal A, luminal B, basal-like, and HER2 [40-45], with (RFS) [7]. subgroups increasingly being identified such as claudin- The recognition of human epidermal growth low and normal breast-like [46-49]. Each subtype displays factor receptor type 2 (HER2, Gene Symbol HER2; unique patterns of metastatic spread associated with located on chromosome 17q12) over-expression as a notable differences in survival after relapse [50]. Clinically, therapeutic target for advanced breast carcinoma was HER2-positive tumors comprise approximately 12–30% primarily related to the clinical finding that HER2/neu of all invasive BCs and are most often found in younger proto-oncogene is amplified in 15–25% of all breast patients and associated with poorer clinical outcomes tumors, and is often associated with poor disease-free [51, 52]. This subtype is associated with increased cell survival (DFS) [8-15]. The mechanism by which HER2 proliferation, angiogenesis, tumor invasiveness, and a high overexpression imparts increased aggressiveness to tumors nuclear grade [53]. It has been observed that patients with has been attributed mostly to dysregulated activation of HER2-positive tumors are more likely to have multifocal/ downstream intracellular signaling pathways [16-25]. In multicentric cancers and nodal involvement [54]. At the some cases HER2 overexpression has been reported to molecular level, HER2-positive BCs exhibits extensive induce resistance to certain chemotherapeutics [26-28]. changes in the patterns of gene expression associated with Furthermore, HER2 overexpression has been found in the HER2 pathway and/or HER2 amplicon located in the both in the primary tumor, circulating tumor cells (CTCs) 17q12 chromosome. The manifestation of the variation in and corresponding metastases [29-31]. the expression of specific subsets of genes exclusive to A high level of correlation was observed between HER2-positive BC is reflected mainly in the variation in HER2 and uPAR mRNA in disseminated tumor cells growth rate, activity of specific signaling pathways, and (DTCs) in 8 out of 16 patients (50%) and was associated in the cellular composition of the tumors [40]. Several with a more aggressive primary tumor phenotype signaling pathways are triggered in HER2-positive BC (estrogen receptor (ER)-negative, progesterone receptor [55-57]. A detailed description of HER2-positive BC (PR)-negative or HER2-positive) [32]. Also a positive subtype can be found
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