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Bergamaschi, Anna,Kim, Young H.,Kwei, Kevin A.,La Choi, Yoon,Bocanegra, Melanie,Langerød, Anita,Han, Wonshik,Noh, Dong-Young,Huntsman, David G.,Jeffrey, Stefanie S.,Børresen-Dale, Anne-Lise,Pollack, J Elsevier 2008 Molecular Oncology Vol.2 No.4
<P><B>Abstract</B></P><P>Breast cancer exhibits clinical and molecular heterogeneity, where expression profiling studies have identified five major molecular subtypes. The basal-like subtype, expressing basal epithelial markers and negative for estrogen receptor (ER), progesterone receptor (PR) and HER2, is associated with higher overall levels of DNA copy number alteration (CNA), specific CNAs (like gain on chromosome 10p), and poor prognosis. Discovering the molecular genetic basis of tumor subtypes may provide new opportunities for therapy. To identify the driver oncogene on 10p associated with basal-like tumors, we analyzed genomic profiles of 172 breast carcinomas. The smallest shared region of gain spanned just seven genes at 10p13, including calcium/calmodulin-dependent protein kinase ID (<I>CAMK1D</I>), functioning in intracellular signaling but not previously linked to cancer. By microarray, <I>CAMK1D</I> was overexpressed when amplified, and by immunohistochemistry exhibited elevated expression in invasive carcinomas compared to carcinoma <I>in situ</I>. Engineered overexpression of CAMK1D in non-tumorigenic breast epithelial cells led to increased cell proliferation, and molecular and phenotypic alterations indicative of epithelial–mesenchymal transition (EMT), including loss of cell–cell adhesions and increased cell migration and invasion. Our findings identify <I>CAMK1D</I> as a novel amplified oncogene linked to EMT in breast cancer, and as a potential therapeutic target with particular relevance to clinically unfavorable basal-like tumors.</P>
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Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency
Davies, Helen,Morganella, Sandro,Purdie, Colin A.,Jang, Se Jin,Borgen, Elin,Russnes, Hege,Glodzik, Dominik,Zou, Xueqing,Viari, Alain,Richardson, Andrea L.,Børresen-Dale, Anne-Lise,Thompson, Alastair,E American Association for Cancer Research 2017 Cancer Research Vol.77 No.18
<P>The effectiveness of PD-1 blockade against DNA mismatch repair-deficient cancers makes it paramount to reliably identify the relatively rare cases beyond those with Lynch syndrome–associated colon cancers.</P><P>Mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. <I>Cancer Res; 77(18); 4755–62. ©2017 AACR</I>.</P>
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Focal amplification and oncogene dependency of GAB2 in breast cancer
Bocanegra, M,Bergamaschi, A,Kim, Y H,Miller, M A,Rajput, A B,Kao, J,Langerød, A,Han, W,Noh, D -Y,Jeffrey, S S,Huntsman, D G,Børresen-Dale, A -L,Pollack, J R Macmillan Publishers Limited 2010 Oncogene Vol.29 No.5
DNA amplifications in breast cancer are frequent on chromosome 11q, in which multiple driver oncogenes likely reside in addition to cyclin D1 (CCND1). One such candidate, the scaffolding adapter protein, GRB2-associated binding protein 2 (GAB2), functions in ErbB signaling and was recently shown to enhance mammary epithelial cell proliferation, and metastasis of ERBB2 (HER2/neu)-driven murine breast cancer. However, the amplification status and function of GAB2 in the context of amplification remain undefined. In this study, by genomic profiling of 172 breast tumors, and fluorescence in situ hybridization validation in an independent set of 210 scorable cases, we observed focal amplification spanning GAB2 (11q14.1) independent of CCND1 (11q13.2) amplification, consistent with a driver role. Further, small interfering RNA (siRNA)-mediated knockdown of GAB2 in breast cancer lines (SUM52, SUM44PE and MDA468) with GAB2 amplification revealed a dependency on GAB2 for cell proliferation, cell-cycle progression, survival and invasion, likely mediated through altered phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling. GAB2 knockdown also reduced proliferation and survival in a cell line (BT474) with ERBB2 amplification, consistent with the possibility that GAB2 can function downstream of ERBB2. Our studies implicate focal amplification of GAB2 in breast carcinogenesis, and underscore an oncogenic role of scaffolding adapter proteins, and a potential new point of therapeutic intervention.
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