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Polyak, Kornelia

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Polyak

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Kornelia

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Polyak, Kornelia
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Now showing 1 - 10 of 18
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    Non-cell autonomous tumor-growth driving supports sub-clonal heterogeneity
    (2014) Marusyk, Andriy; Tabassum, Doris P.; Altrock, Philipp; Almendro, Vanessa; Michor, Franziska; Polyak, Kornelia
    SUMMARY Cancers arise through a process of somatic evolution that can result in substantial sub-clonal heterogeneity within tumors. The mechanisms responsible for the coexistence of distinct sub-clones and the biological consequences of this coexistence remain poorly understood. Here we used a mouse xenograft model to investigate the impact of sub-clonal heterogeneity on tumor phenotypes and the competitive expansion of individual clones. We found that tumor growth can be driven by a minor cell subpopulation, which enhances the proliferation of all cells within a tumor by overcoming environmental constraints and yet can be outcompeted by faster proliferating competitors, resulting in tumor collapse. We then developed a mathematical modeling framework to identify the rules underlying the generation of intratumor clonal heterogeneity. We found that non-cell autonomous driving, together with clonal interference, stabilizes sub-clonal heterogeneity, thereby enabling inter-clonal interactions that can lead to new phenotypic traits.
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    In situ single cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2+ breast cancer
    (2015) Janiszewska, Michalina; Liu, Lin; Almendro, Vanessa; Kuang, Yanan; Paweletz, Cloud; Sakr, Rita A.; Weigelt, Britta; Hanker, Ariella B.; Chandarlapaty, Sarat; King, Tari A.; Reis-Filho, Jorge S.; Arteaga, Carlos L.; Park, So Yeon; Michor, Franziska; Polyak, Kornelia
    Detection of minor genetically distinct subpopulations within tumors is a key challenge in cancer genomics. Here we report STAR-FISH (Specific-To-Allele PCR – FISH), a novel method for the combined detection of single nucleotide and copy number alterations in single cells in intact archived tissues. Using this method, we assessed the clinical impact of changes in the frequency and topology of PIK3CA mutation and HER2/ERBB2 amplification within HER2+ breast cancer during neoadjuvant therapy. We found that the two genetic events are not always present within the same cell. Chemotherapy selects for PIK3CA mutant cells, a minor subpopulation in nearly all treatment-naïve samples, and modulates genetic diversity within tumors. Treatment-associated changes in spatial distribution of cellular genetic diversity correlated with poor long-term outcome following adjuvant trastuzumab therapy. Our findings support the use of in situ single-cell based methods in cancer genomics and imply that chemotherapy before HER2-targeted therapy may promote treatment resistance.
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    Dissecting the mammary gland one cell at a time
    (Nature Publishing Group UK, 2018) Cristea, Simona; Polyak, Kornelia
    Dissecting cellular differentiation hierarchies in the mammary gland is a prerequisite for understanding both normal development and malignant transformation during tumorigenesis and tumor cell-of-origin. To achieve these goals, several recent papers utilized single cell RNA-seq and lineage tracing to improve our understanding of the composition of the mammary epithelium at different developmental stages.
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    BRCA1 haploinsufficiency for replication stress suppression in primary cells
    (Nature Pub. Group, 2014) Pathania, Shailja; Bade, Sangeeta; Le Guillou, Morwenna; Burke, Karly; Reed, Rachel; Bowman-Colin, Christian; Su, Ying; Ting, David; Polyak, Kornelia; Richardson, Andrea; Feunteun, Jean; Garber, Judy; Livingston, David
    BRCA1—a breast and ovarian cancer suppressor gene—promotes genome integrity. To study the functionality of BRCA1 in the heterozygous state, we established a collection of primary human BRCA1+/+ and BRCA1mut/+ mammary epithelial cells and fibroblasts. Here we report that all BRCA1mut/+ cells exhibited multiple normal BRCA1 functions, including the support of homologous recombination- type double-strand break repair (HR-DSBR), checkpoint functions, centrosome number control, spindle pole formation, Slug expression and satellite RNA suppression. In contrast, the same cells were defective in stalled replication fork repair and/or suppression of fork collapse, that is, replication stress. These defects were rescued by reconstituting BRCA1mut/+ cells with wt BRCA1. In addition, we observed ‘conditional’ haploinsufficiency for HR-DSBR in BRCA1mut/+ cells in the face of replication stress. Given the importance of replication stress in epithelial cancer development and of an HR defect in breast cancer pathogenesis, both defects are candidate contributors to tumorigenesis in BRCA1-deficient mammary tissue.
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    Age- and Pregnancy-Associated DNA Methylation Changes in Mammary Epithelial Cells
    (Elsevier, 2015) Huh, Sung Jin; Clement, Kendell; Jee, David; Merlini, Alessandra; Choudhury, Sibgat; Maruyama, Reo; Yoo, Ronnie; Chytil, Anna; Boyle, Patrick; Ran, Fei Ann; Moses, Harold L.; Barcellos-Hoff, Mary Helen; Jackson-Grusby, Laurie; Meissner, Alexander; Polyak, Kornelia
    Summary Postnatal mammary gland development and differentiation occur during puberty and pregnancy. To explore the role of DNA methylation in these processes, we determined the genome-wide DNA methylation and gene expression profiles of CD24+CD61+CD29hi, CD24+CD61+CD29lo, and CD24+CD61−CD29lo cell populations that were previously associated with distinct biological properties at different ages and reproductive stages. We found that pregnancy had the most significant effects on CD24+CD61+CD29hi and CD24+CD61+CD29lo cells, inducing distinct epigenetic states that were maintained through life. Integrated analysis of gene expression, DNA methylation, and histone modification profiles revealed cell-type- and reproductive-stage-specific changes. We identified p27 and TGFβ signaling as key regulators of CD24+CD61+CD29lo cell proliferation, based on their expression patterns and results from mammary gland explant cultures. Our results suggest that relatively minor changes in DNA methylation occur during luminal differentiation compared with the effects of pregnancy on CD24+CD61+CD29hi and CD24+CD61+CD29lo cells.
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    Gene expression profiling of human breast tissue samples using SAGE-Seq
    (Cold Spring Harbor Laboratory Press, 2010) Wu, Z. J.; Meyer, Clifford; Choudhury, S.; Shipitsin, M.; Maruyama, R.; Bessarabova, M.; Nikolskaya, T.; Sukumar, S.; Schwartzman, A.; Liu, Jun; Polyak, Kornelia; Liu, Xiaole
    We present a powerful application of ultra high-throughput sequencing, SAGE-Seq, for the accurate quantification of normal and neoplastic mammary epithelial cell transcriptomes. We develop data analysis pipelines that allow the mapping of sense and antisense strands of mitochondrial and RefSeq genes, the normalization between libraries, and the identification of differentially expressed genes. We find that the diversity of cancer transcriptomes is significantly higher than that of normal cells. Our analysis indicates that transcript discovery plateaus at 10 million reads/sample, and suggests a minimum desired sequencing depth around five million reads. Comparison of SAGE-Seq and traditional SAGE on normal and cancerous breast tissues reveals higher sensitivity of SAGE-Seq to detect less-abundant genes, including those encoding for known breast cancer-related transcription factors and G protein–coupled receptors (GPCRs). SAGE-Seq is able to identify genes and pathways abnormally activated in breast cancer that traditional SAGE failed to call. SAGE-Seq is a powerful method for the identification of biomarkers and therapeutic targets in human disease.
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    Dermcidin exerts its oncogenic effects in breast cancer via modulation of ERBB signaling
    (BioMed Central, 2015) Bancovik, Jasna; Moreira, Dayson F; Carrasco, Daniel; Yao, Jun; Porter, Dale; Moura, Ricardo; Camargo, Anamaria; Fontes-Oliveira, Cibely C; Malpartida, Miguel G; Carambula, Silvia; Vannier, Edouard; Strauss, Bryan E; Wakamatsu, Alda; Alves, Venancio AF; Logullo, Angela F; Soares, Fernando A; Polyak, Kornelia; Belizário, José E
    Background: We previously identified dermicidin (DCD), which encodes a growth and survival factor, as a gene amplified and overexpressed in a subset of breast tumors. Patients with DCD-positive breast cancer have worse prognostic features. We therefore searched for specific molecular signatures in DCD-positive breast carcinomas from patients and representative cell lines. Methods: DCD expression was evaluated by qRT-PCR, immunohistochemical and immunoblot assays in normal and neoplastic tissues and cell lines. To investigate the role of DCD in breast tumorigenesis, we analyzed the consequences of its downregulation in human breast cancer cell lines using three specific shRNA lentiviral vectors. Genes up- and down-regulated by DCD were identified using Affymetrix microarray and analyzed by MetaCore Platform. Results: We identified DCD splice variant (DCD-SV) that is co-expressed with DCD in primary invasive breast carcinomas and in other tissue types and cell lines. DCD expression in breast tumors from patients with clinical follow up data correlated with high histological grade, HER2 amplification and luminal subtype. We found that loss of DCD expression led to reduced cell proliferation, resistance to apoptosis, and suppressed tumorigenesis in immunodeficient mice. Network analysis of gene expression data revealed perturbed ERBB signaling following DCD shRNA expression including changes in the expression of ERBB receptors and their ligands. Conclusions: These findings imply that DCD promotes breast tumorigenesis via modulation of ERBB signaling pathways. As ERBB signaling is also important for neural survival, HER2+ breast tumors may highjack DCD’s neural survival-promoting functions to promote tumorigenesis. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1022-6) contains supplementary material, which is available to authorized users.
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    Response and resistance to BET bromodomain inhibitors in triple negative breast cancer
    (2015) Shu, Shaokun; Lin, Charles Y.; He, Housheng Hansen; Witwicki, Robert; Tabassum, Doris P.; Roberts, Justin M.; Janiszewska, Michalina; Huh, Sung Jin; Liang, Yi; Ryan, Jeremy; Doherty, Ernest; Mohammed, Hisham; Guo, Hao; Stover, Daniel G.; Ekram, Muhammad B.; Brown, Jonathan; D'Santos, Clive; Krop, Ian; Dillon, Deborah; McKeown, Michael; Ott, Christopher; Qi, Jun; Ni, Min; Rao, Prakash K.; Duarte, Melissa; Wu, Shwu-Yuan; Chiang, Cheng-Ming; Anders, Lars; Young, Richard A.; Winer, Eric; Letai, Antony; Barry, William T.; Carroll, Jason S.; Long, Henry; Brown, Myles; Liu, X. Shirley; Meyer, Clifford; Bradner, James E; Polyak, Kornelia
    Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy1-3. BET bromodomain inhibitors, which have shown efficacy in several models of cancer4-6, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyllysine recognition modules, leading to inhibition of oncogenic transcriptional programs7-9. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance.
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    Expression of estrogen receptor, progesterone receptor, and Ki67 in normal breast tissue in relation to subsequent risk of breast cancer
    (2016) Oh, Hannah; Eliassen, A; Wang, Molin; Smith-Warner, Stephanie; Beck, Andrew; Schnitt, Stuart; Collins, Laura; Connolly, James; Montaser-Kouhsari, Laleh; Polyak, Kornelia; Tamimi, Rulla
    Although expression of estrogen receptor (ER), progesterone receptor (PR), and cell proliferation marker Ki67 serve as predictive and prognostic factors in breast cancers, little is known about their roles in normal breast tissue. Here in a nested case–control study within the Nurses’ Health Studies (90 cases, 297 controls), we evaluated their expression levels in normal breast epithelium in relation to subsequent breast cancer risk among women with benign breast disease. Tissue microarrays were constructed using cores obtained from benign biopsies containing normal terminal duct lobular units and immunohistochemical stained for these markers. We found PR and Ki67 expression was non-significantly but positively associated with subsequent breast cancer risk, whereas ER expression was non-significantly inversely associated. After stratifying by lesion subtype, Ki67 was significantly associated with higher risk among women with proliferative lesions with atypical hyperplasia. However, given the small sample size, further studies are required to confirm these results.
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    PAK1 is a Breast Cancer Oncogene that Coordinately Activates MAPK and MET Signaling
    (Nature Publishing Group, 2012) Shrestha, Yashaswi; Schafer, Eric J.; Boehm, Jesse S.; He, Frank; Wang, Shumei; Barretina, Jordi; Thomas, Sapana Rachael; Du, Jinyan; Weir, Barbara Ann; Zhao, Jean; Golub, Todd; Beroukhim, Rameen; Hahn, William; Polyak, Kornelia
    Activating mutations in the RAS family or BRAF frequently occur in many types of human cancers but are rarely detected in breast tumors. However, activation of the RAS-RAF-MEK-ERK Mitogen-Activated Protein Kinase (MAPK) pathway is commonly observed in human breast cancers, suggesting that other genetic alterations lead to activation of this signaling pathway. To identify breast cancer oncogenes that activate the MAPK pathway, we screened a library of human kinases for their ability to induce anchorage-independent growth in a derivative of immortalized human mammary epithelial cells (HMLE). We identified PAK1 as a kinase that permitted HMLE cells to form anchorage-independent colonies. PAK1 is amplified in several human cancer types, including 33% of breast tumor samples and cancer cell lines. The kinase activity of PAK1 is necessary for PAK1-induced transformation. Moreover, we show that PAK1 simultaneously activates MAPK and MET signaling; the latter via inhibition of Merlin. Disruption of these activities inhibits PAK1-driven anchorage-independent growth. These observations establish PAK1 amplification as an alternative mechanism for MAPK activation in human breast cancer and credential PAK1 as a breast cancer oncogene that coordinately regulates multiple signaling pathways, the cooperation of which leads to malignant transformation.