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1. Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer

Author

Tyler Risom, Ellen M. Langer, Margaret P. Chapman, Juha Rantala, Andrew J. Fields, Christopher Boniface, Mariano J. Alvarez, Nicholas D. Kendsersky, Carl R. Pelz, Katherine Johnson-Camacho, Lacey E. Dobrolecki, Koei Chin, Anil J. Aswani, Nicholas J. Wang, Andrea Califano, Michael T. Lewis, Claire J. Tomlin, Paul T. Spellman, Andrew Adey, Joe W. Gray, and Rosalie C. Sears

Subjects
Science
Abstract

Resistance to therapy can be driven by intratumoral heterogeneity. Here, the authors show that drug tolerant persistent cell populations emerge during treatment, and these emergent populations arise through epigenetically mediated cell state transitions rather than sub population selection.

Published
2018
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2. Patient-specific factors influence somatic variation patterns in von Hippel–Lindau disease renal tumours

Author

Suzanne S. Fei, Asia D. Mitchell, Michael B. Heskett, Cathy D. Vocke, Christopher J. Ricketts, Myron Peto, Nicholas J. Wang, Kemal Sönmez, W. Marston Linehan, and Paul T. Spellman

Subjects
Science
Abstract

Analysing multiple tumours from the same patient permits the study of the germline contribution to cancer. Here, the authors sequence multiple renal tumours from VHL patients and find that intra-patient tumours are clonally distinct but share some genetic features, suggesting that patient-specific factors influence tumour formation.

Published
2016
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3. Transcription Restores DNA Repair to Heterochromatin, Determining Regional Mutation Rates in Cancer Genomes

Author

Christina L. Zheng, Nicholas J. Wang, Jongsuk Chung, Homayoun Moslehi, J. Zachary Sanborn, Joseph S. Hur, Eric A. Collisson, Swapna S. Vemula, Agne Naujokas, Kami E. Chiotti, Jeffrey B. Cheng, Hiva Fassihi, Andrew J. Blumberg, Celeste V. Bailey, Gary M. Fudem, Frederick G. Mihm, Bari B. Cunningham, Isaac M. Neuhaus, Wilson Liao, Dennis H. Oh, James E. Cleaver, Philip E. LeBoit, Joseph F. Costello, Alan R. Lehmann, Joe W. Gray, Paul T. Spellman, Sarah T. Arron, Nam Huh, Elizabeth Purdom, and Raymond J. Cho

Subjects
Biology (General), QH301-705.5
Abstract

Somatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC−/− background. XPC−/− cells lack global genome nucleotide excision repair (GG-NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk.

Published
2014
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4. Supplementary Figure 1 from Temporal Dissection of Tumorigenesis in Primary Cancers

Author

Raymond J. Cho, Paul T. Spellman, Joe W. Gray, Sarah T. Arron, Lars Bolund, Jian Li, Elizabeth Purdom, Haiyan Huang, Jon C. Aster, Kristian Cibulskis, Gad Getz, Philip E. LeBoit, Pui-Yan Kwok, James E. Cleaver, Theodora M. Mauro, Roy C. Grekin, Siegrid S. Yu, Isaac M. Neuhaus, Nam Huh, Joe S. Hur, Sung-woo Hong, Kyunghee Park, Catherine Chu, Ernest T. Lam, Sai-Wing Chan, Jennifer Pons, Eric A. Collisson, Lakshmi R. Jakkula, Wilson Liao, Nicholas J. Wang, Christine Ho, and Steffen Durinck

Abstract

Supplementary Figure 1 from Temporal Dissection of Tumorigenesis in Primary Cancers

Published
2023

5. Supplementary Figure 2 from Temporal Dissection of Tumorigenesis in Primary Cancers

Author

Raymond J. Cho, Paul T. Spellman, Joe W. Gray, Sarah T. Arron, Lars Bolund, Jian Li, Elizabeth Purdom, Haiyan Huang, Jon C. Aster, Kristian Cibulskis, Gad Getz, Philip E. LeBoit, Pui-Yan Kwok, James E. Cleaver, Theodora M. Mauro, Roy C. Grekin, Siegrid S. Yu, Isaac M. Neuhaus, Nam Huh, Joe S. Hur, Sung-woo Hong, Kyunghee Park, Catherine Chu, Ernest T. Lam, Sai-Wing Chan, Jennifer Pons, Eric A. Collisson, Lakshmi R. Jakkula, Wilson Liao, Nicholas J. Wang, Christine Ho, and Steffen Durinck

Abstract

Supplementary Figure 2 from Temporal Dissection of Tumorigenesis in Primary Cancers

Published
2023

6. Supplementary Figure Legends 1-4, Methods from Temporal Dissection of Tumorigenesis in Primary Cancers

Author

Raymond J. Cho, Paul T. Spellman, Joe W. Gray, Sarah T. Arron, Lars Bolund, Jian Li, Elizabeth Purdom, Haiyan Huang, Jon C. Aster, Kristian Cibulskis, Gad Getz, Philip E. LeBoit, Pui-Yan Kwok, James E. Cleaver, Theodora M. Mauro, Roy C. Grekin, Siegrid S. Yu, Isaac M. Neuhaus, Nam Huh, Joe S. Hur, Sung-woo Hong, Kyunghee Park, Catherine Chu, Ernest T. Lam, Sai-Wing Chan, Jennifer Pons, Eric A. Collisson, Lakshmi R. Jakkula, Wilson Liao, Nicholas J. Wang, Christine Ho, and Steffen Durinck

Abstract

Supplementary Figure Legends 1-4, Methods from Temporal Dissection of Tumorigenesis in Primary Cancers

Published
2023

7. Supplementary Table 2 from Temporal Dissection of Tumorigenesis in Primary Cancers

Author

Raymond J. Cho, Paul T. Spellman, Joe W. Gray, Sarah T. Arron, Lars Bolund, Jian Li, Elizabeth Purdom, Haiyan Huang, Jon C. Aster, Kristian Cibulskis, Gad Getz, Philip E. LeBoit, Pui-Yan Kwok, James E. Cleaver, Theodora M. Mauro, Roy C. Grekin, Siegrid S. Yu, Isaac M. Neuhaus, Nam Huh, Joe S. Hur, Sung-woo Hong, Kyunghee Park, Catherine Chu, Ernest T. Lam, Sai-Wing Chan, Jennifer Pons, Eric A. Collisson, Lakshmi R. Jakkula, Wilson Liao, Nicholas J. Wang, Christine Ho, and Steffen Durinck

Abstract

Supplementary Table 2 from Temporal Dissection of Tumorigenesis in Primary Cancers

Published
2023

8. Supplementary Figure 3 from Temporal Dissection of Tumorigenesis in Primary Cancers

Author

Raymond J. Cho, Paul T. Spellman, Joe W. Gray, Sarah T. Arron, Lars Bolund, Jian Li, Elizabeth Purdom, Haiyan Huang, Jon C. Aster, Kristian Cibulskis, Gad Getz, Philip E. LeBoit, Pui-Yan Kwok, James E. Cleaver, Theodora M. Mauro, Roy C. Grekin, Siegrid S. Yu, Isaac M. Neuhaus, Nam Huh, Joe S. Hur, Sung-woo Hong, Kyunghee Park, Catherine Chu, Ernest T. Lam, Sai-Wing Chan, Jennifer Pons, Eric A. Collisson, Lakshmi R. Jakkula, Wilson Liao, Nicholas J. Wang, Christine Ho, and Steffen Durinck

Abstract

Supplementary Figure 3 from Temporal Dissection of Tumorigenesis in Primary Cancers

Published
2023

9. Supplementary Figure 4 from Temporal Dissection of Tumorigenesis in Primary Cancers

Author

Raymond J. Cho, Paul T. Spellman, Joe W. Gray, Sarah T. Arron, Lars Bolund, Jian Li, Elizabeth Purdom, Haiyan Huang, Jon C. Aster, Kristian Cibulskis, Gad Getz, Philip E. LeBoit, Pui-Yan Kwok, James E. Cleaver, Theodora M. Mauro, Roy C. Grekin, Siegrid S. Yu, Isaac M. Neuhaus, Nam Huh, Joe S. Hur, Sung-woo Hong, Kyunghee Park, Catherine Chu, Ernest T. Lam, Sai-Wing Chan, Jennifer Pons, Eric A. Collisson, Lakshmi R. Jakkula, Wilson Liao, Nicholas J. Wang, Christine Ho, and Steffen Durinck

Abstract

Supplementary Figure 4 from Temporal Dissection of Tumorigenesis in Primary Cancers

Published
2023

10. Supplementary Table 1 from Temporal Dissection of Tumorigenesis in Primary Cancers

Author

Raymond J. Cho, Paul T. Spellman, Joe W. Gray, Sarah T. Arron, Lars Bolund, Jian Li, Elizabeth Purdom, Haiyan Huang, Jon C. Aster, Kristian Cibulskis, Gad Getz, Philip E. LeBoit, Pui-Yan Kwok, James E. Cleaver, Theodora M. Mauro, Roy C. Grekin, Siegrid S. Yu, Isaac M. Neuhaus, Nam Huh, Joe S. Hur, Sung-woo Hong, Kyunghee Park, Catherine Chu, Ernest T. Lam, Sai-Wing Chan, Jennifer Pons, Eric A. Collisson, Lakshmi R. Jakkula, Wilson Liao, Nicholas J. Wang, Christine Ho, and Steffen Durinck

Abstract

Supplementary Table 1 from Temporal Dissection of Tumorigenesis in Primary Cancers

Published
2023

11. Supplementary Figure 2 from Upregulation of ER Signaling as an Adaptive Mechanism of Cell Survival in HER2-Positive Breast Tumors Treated with Anti-HER2 Therapy

Author

Rachel Schiff, Mothaffar F. Rimawi, C. Kent Osborne, Jenny C. Chang, Gary C. Chamness, Meghana V. Trivedi, Anne C. Pavlick, Sara Lopez-Tarruella, Joe W. Gray, Laura M. Heiser, Nicholas J. Wang, Carmine De Angelis, Susan G. Hilsenbeck, Tao Wang, Carolina Gutierrez, Alejandro Contreras, Sufeng Mao, Sabrina Herrera, Agostina Nardone, Xiaoyong Fu, Yen-Chao Wang, Huizhong Hu, and Mario Giuliano

Abstract

Supplementary Figure 2. ER expression changes upon neoadjuvant treatment with trastuzumab

Published
2023

12. Data from Upregulation of ER Signaling as an Adaptive Mechanism of Cell Survival in HER2-Positive Breast Tumors Treated with Anti-HER2 Therapy

Author

Rachel Schiff, Mothaffar F. Rimawi, C. Kent Osborne, Jenny C. Chang, Gary C. Chamness, Meghana V. Trivedi, Anne C. Pavlick, Sara Lopez-Tarruella, Joe W. Gray, Laura M. Heiser, Nicholas J. Wang, Carmine De Angelis, Susan G. Hilsenbeck, Tao Wang, Carolina Gutierrez, Alejandro Contreras, Sufeng Mao, Sabrina Herrera, Agostina Nardone, Xiaoyong Fu, Yen-Chao Wang, Huizhong Hu, and Mario Giuliano

Abstract

Purpose: To investigate the direct effect and therapeutic consequences of epidermal growth factor receptor 2 (HER2)-targeting therapy on expression of estrogen receptor (ER) and Bcl2 in preclinical models and clinical tumor samples.Experimental design: Archived xenograft tumors from two preclinical models (UACC812 and MCF7/HER2-18) treated with ER and HER2-targeting therapies and also HER2+ clinical breast cancer specimens collected in a lapatinib neoadjuvant trial (baseline and week 2 posttreatment) were used. Expression levels of ER and Bcl2 were evaluated by immunohistochemistry and Western blot analysis. The effects of Bcl2 and ER inhibition, by ABT-737 and fulvestrant, respectively, were tested in parental versus lapatinib-resistant UACC812 cells in vitro.Results: Expression of ER and Bcl2 was significantly increased in xenograft tumors with acquired resistance to anti-HER2 therapy compared with untreated tumors in both preclinical models (UACC812: ER P = 0.0014; Bcl2 P < 0.001 and MCF7/HER2-18: ER P = 0.0007; Bcl2 P = 0.0306). In the neoadjuvant clinical study, lapatinib treatment for 2 weeks was associated with parallel upregulation of ER and Bcl2 (Spearman coefficient: 0.70; P = 0.0002). Importantly, 18% of tumors originally ER-negative (ER−) converted to ER+ upon anti-HER2 therapy. In ER−/HER2+ MCF7/HER2-18 xenografts, ER reexpression was primarily observed in tumors responding to potent combination of anti-HER2 drugs. Estrogen deprivation added to this anti-HER2 regimen significantly delayed tumor progression (P = 0.018). In the UACC812 cells, fulvestrant, but not ABT-737, was able to completely inhibit anti–HER2-resistant growth (P < 0.0001).Conclusions: HER2 inhibition can enhance or restore ER expression with parallel Bcl2 upregulation, representing an ER-dependent survival mechanism potentially leading to anti-HER2 resistance. Clin Cancer Res; 21(17); 3995–4003. ©2015 AACR.

Published
2023

13. Supplementary figure legend from Upregulation of ER Signaling as an Adaptive Mechanism of Cell Survival in HER2-Positive Breast Tumors Treated with Anti-HER2 Therapy

Author

Rachel Schiff, Mothaffar F. Rimawi, C. Kent Osborne, Jenny C. Chang, Gary C. Chamness, Meghana V. Trivedi, Anne C. Pavlick, Sara Lopez-Tarruella, Joe W. Gray, Laura M. Heiser, Nicholas J. Wang, Carmine De Angelis, Susan G. Hilsenbeck, Tao Wang, Carolina Gutierrez, Alejandro Contreras, Sufeng Mao, Sabrina Herrera, Agostina Nardone, Xiaoyong Fu, Yen-Chao Wang, Huizhong Hu, and Mario Giuliano

Abstract

Supplementary figure legend. Legend of supplementary Figure 1 and 2

Published
2023

14. Supplementary Figure 1 from Upregulation of ER Signaling as an Adaptive Mechanism of Cell Survival in HER2-Positive Breast Tumors Treated with Anti-HER2 Therapy

Author

Rachel Schiff, Mothaffar F. Rimawi, C. Kent Osborne, Jenny C. Chang, Gary C. Chamness, Meghana V. Trivedi, Anne C. Pavlick, Sara Lopez-Tarruella, Joe W. Gray, Laura M. Heiser, Nicholas J. Wang, Carmine De Angelis, Susan G. Hilsenbeck, Tao Wang, Carolina Gutierrez, Alejandro Contreras, Sufeng Mao, Sabrina Herrera, Agostina Nardone, Xiaoyong Fu, Yen-Chao Wang, Huizhong Hu, and Mario Giuliano

Abstract

Supplementary Figure 1. Lapatinib clinical trial scheme

Published
2023

15. Supplemental Tables 1, 2, 3 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplemental Tables 1, 2, 3

Published
2023

16. Supplemental Figure 6B from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplemental Figure 6A

Published
2023

17. Supplemental Figure 3 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplemental Figure 3

Published
2023

18. Supplemental Table 8 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplemental Table 8

Published
2023

19. Supplemental Table 7 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplemental Table 7

Published
2023

20. Supplementary Table 4 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplementary Table 4 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Published
2023

21. Supplementary Tables 1-3 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplementary Tables 1-3 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Published
2023

22. Supplemental Figure and Table Legends from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplemental Figure and Table Legends

Published
2023

23. Supplemental Figure 2 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplemental Figure 2

Published
2023

24. Supplemental Table 6 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplemental Table 6

Published
2023

25. Supplementary Figure Legends 1-2 from Basal Subtype and MAPK/ERK Kinase (MEK)-Phosphoinositide 3-Kinase Feedback Signaling Determine Susceptibility of Breast Cancer Cells to MEK Inhibition

Author

W. Michael Korn, Joe W. Gray, Gordon B. Mills, Wen-Lin Kuo, Frank McCormick, Mina J. Bissell, Andrew J. Wyrobek, Kevan M. Shokat, Paul T. Spellman, Bahram Parvin, Philippe Gascard, Heidi S. Feiler, Zachary Knight, Zhi Hu, Yinghui Guan, Richard M. Neve, Nicholas J. Wang, Nora Bayani, Rina Gendelman, Doris Siwak, Sanchita Bhattacharya, Laura M. Heiser, Debopriya Das, and Olga K. Mirzoeva

Abstract

Supplementary Figure Legends 1-2 from Basal Subtype and MAPK/ERK Kinase (MEK)-Phosphoinositide 3-Kinase Feedback Signaling Determine Susceptibility of Breast Cancer Cells to MEK Inhibition

Published
2023

26. Data from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor–positive cancers (34.5%; P = 0.32), 17 of 75 HER-2–positive samples (22.7%; P = 0.04), 20 of 240 basal-like cancers (8.3%; P < 0.0001), and 0 of 14 claudin-low tumors (P = 0.004). Of 7 phosphatidylinositol 3-kinase/AKT pathway phosphorylation sites, 6 were more highly phosphorylated in MBCs than in other breast tumor subtypes. The majority of MBCs displayed mRNA profiles different from those of the most common, including basal-like cancers. By transcriptional profiling, MBCs and the recently identified claudin-low breast cancer subset constitute related receptor-negative subgroups characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and epithelial-to-mesenchymal transition (EMT). In contrast to other breast cancers, claudin-low tumors and most MBCs showed a significant similarity to a “tumorigenic” signature defined using CD44+/CD24− breast tumor–initiating stem cell–like cells. MBCs and claudin-low tumors are thus enriched in EMT and stem cell–like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and suggest novel therapeutic targets. [Cancer Res 2009;69(10):4116–24]

Published
2023

27. Supplementary Figure 1 from Basal Subtype and MAPK/ERK Kinase (MEK)-Phosphoinositide 3-Kinase Feedback Signaling Determine Susceptibility of Breast Cancer Cells to MEK Inhibition

Author

W. Michael Korn, Joe W. Gray, Gordon B. Mills, Wen-Lin Kuo, Frank McCormick, Mina J. Bissell, Andrew J. Wyrobek, Kevan M. Shokat, Paul T. Spellman, Bahram Parvin, Philippe Gascard, Heidi S. Feiler, Zachary Knight, Zhi Hu, Yinghui Guan, Richard M. Neve, Nicholas J. Wang, Nora Bayani, Rina Gendelman, Doris Siwak, Sanchita Bhattacharya, Laura M. Heiser, Debopriya Das, and Olga K. Mirzoeva

Abstract

Supplementary Figure 1 from Basal Subtype and MAPK/ERK Kinase (MEK)-Phosphoinositide 3-Kinase Feedback Signaling Determine Susceptibility of Breast Cancer Cells to MEK Inhibition

Published
2023

28. Supplemental Figure 1 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplemental Figure 1

Published
2023

29. Supplementary Legends for Figures and Tables 1-8 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplementary Legends for Figures and Tables 1-8 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Published
2023

30. Supplementary Tables 5-8 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplementary Tables 5-8 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Published
2023

31. Supplementary Tables 1-6 from Basal Subtype and MAPK/ERK Kinase (MEK)-Phosphoinositide 3-Kinase Feedback Signaling Determine Susceptibility of Breast Cancer Cells to MEK Inhibition

Author

W. Michael Korn, Joe W. Gray, Gordon B. Mills, Wen-Lin Kuo, Frank McCormick, Mina J. Bissell, Andrew J. Wyrobek, Kevan M. Shokat, Paul T. Spellman, Bahram Parvin, Philippe Gascard, Heidi S. Feiler, Zachary Knight, Zhi Hu, Yinghui Guan, Richard M. Neve, Nicholas J. Wang, Nora Bayani, Rina Gendelman, Doris Siwak, Sanchita Bhattacharya, Laura M. Heiser, Debopriya Das, and Olga K. Mirzoeva

Abstract

Supplementary Tables 1-6 from Basal Subtype and MAPK/ERK Kinase (MEK)-Phosphoinositide 3-Kinase Feedback Signaling Determine Susceptibility of Breast Cancer Cells to MEK Inhibition

Published
2023

32. Supplemental Figure 7 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplemental Figure 7 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Published
2023

33. Supplementary Figure 4 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplementary Figure 4 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Published
2023

34. Supplementary Figures 5 and 6A-B from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplementary Figures 5 and 6A-B from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Published
2023

35. Supplemental Figure 8 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplemental Figure 8

Published
2023

36. Supplemental Table 5 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplemental Table 5

Published
2023

37. Supplementary Figure 2 from Basal Subtype and MAPK/ERK Kinase (MEK)-Phosphoinositide 3-Kinase Feedback Signaling Determine Susceptibility of Breast Cancer Cells to MEK Inhibition

Author

W. Michael Korn, Joe W. Gray, Gordon B. Mills, Wen-Lin Kuo, Frank McCormick, Mina J. Bissell, Andrew J. Wyrobek, Kevan M. Shokat, Paul T. Spellman, Bahram Parvin, Philippe Gascard, Heidi S. Feiler, Zachary Knight, Zhi Hu, Yinghui Guan, Richard M. Neve, Nicholas J. Wang, Nora Bayani, Rina Gendelman, Doris Siwak, Sanchita Bhattacharya, Laura M. Heiser, Debopriya Das, and Olga K. Mirzoeva

Abstract

Supplementary Figure 2 from Basal Subtype and MAPK/ERK Kinase (MEK)-Phosphoinositide 3-Kinase Feedback Signaling Determine Susceptibility of Breast Cancer Cells to MEK Inhibition

Published
2023

38. Conflict of Interest Form 1 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Conflict of Interest Form 1 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Published
2023

39. Supplemental Figure 5 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Author

Gordon B. Mills, Charles M. Perou, Joe W. Gray, Vicente Valero, Nicholas J. Wang, Laura K. Nolden, Gabriel N. Hortobagyi, Juan Palazzo, Cheng Fan, Victor Weigman, Xiaping He, Carlos Monteagudo, Ana Lluch, Mark Carey, Keith Baggerly, David Stivers, Wenbin Liu, Corwin Joy, Roshan Agarwal, Aysegul Sahin, Jane Fridlyand, Ju-Seog Lee, Savitri Krishnamurthy, Michael Z. Gilcrease, Katherine Stemke-Hale, Ana-Maria Gonzalez-Angulo, and Bryan T. Hennessy

Abstract

Supplemental Figure 5 from Characterization of a Naturally Occurring Breast Cancer Subset Enriched in Epithelial-to-Mesenchymal Transition and Stem Cell Characteristics

Published
2023

44. Targeting the Mevalonate Pathway to Overcome Acquired Anti-HER2 Treatment Resistance in Breast Cancer

Author

Xiaoyong Fu, Shixia Huang, Resel Pereira, Nicholas J. Wang, Chad A. Shaw, Jorge S. Reis-Filho, Sarmistha Nanda, Anna Tsimelzon, Agostina Nardone, Vidyalakshmi Sethunath, Rachel Schiff, Laura M. Heiser, Britta Weigelt, Lukas M. Simon, Joe W. Gray, Carmine De Angelis, Tao Wang, Mothaffar F. Rimawi, Lanfang Qin, Gary C. Chamness, Obi L. Griffith, Jamunarani Veeraraghavan, Huizhong Hu, C. Kent Osborne, Susan G. Hilsenbeck, Sethunath, Vidyalakshmi, Hu, Huizhong, DE ANGELIS, Carmine, Veeraraghavan, Jamunarani, Qin, Lanfang, Wang, Nichola, Simon, Lukas M, Wang, Tao, Fu, Xiaoyong, Nardone, Agostina, Pereira, Resel, Nanda, Sarmistha, Griffith, Obi L, Tsimelzon, Anna, Shaw, Chad, Chamness, Gary C, Reis-Filho, Jorge S, Weigelt, Britta, Heiser, Laura M, Hilsenbeck, Susan G, Huang, Shixia, Rimawi, Mothaffar F, Gray, Joe W, Osborne, C Kent, and Schiff, Rachel

Subjects
0301 basic medicine, Cancer Research, Geranylgeranyl pyrophosphate, Receptor, ErbB-2, Farnesyl pyrophosphate, Mevalonic Acid, Antineoplastic Agents, Apoptosis, Breast Neoplasms, Mechanistic Target of Rapamycin Complex 1, Lapatinib, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cell Line, Tumor, Survivin, Humans, Medicine, Phosphorylation, skin and connective tissue diseases, neoplasms, Molecular Biology, business.industry, Cell growth, Trastuzumab, 030104 developmental biology, Oncology, chemistry, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer research, Female, Mevalonate pathway, Growth inhibition, business, Signal Transduction, medicine.drug
Abstract

Despite effective strategies, resistance in HER2+ breast cancer remains a challenge. While the mevalonate pathway (MVA) is suggested to promote cell growth and survival, including in HER2+ models, its potential role in resistance to HER2-targeted therapy is unknown. Parental HER2+ breast cancer cells and their lapatinib-resistant and lapatinib + trastuzumab–resistant derivatives were used for this study. MVA activity was found to be increased in lapatinib-resistant and lapatinib + trastuzumab–resistant cells. Specific blockade of this pathway with lipophilic but not hydrophilic statins and with the N-bisphosphonate zoledronic acid led to apoptosis and substantial growth inhibition of R cells. Inhibition was rescued by mevalonate or the intermediate metabolites farnesyl pyrophosphate or geranylgeranyl pyrophosphate, but not cholesterol. Activated Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and mTORC1 signaling, and their downstream target gene product Survivin, were inhibited by MVA blockade, especially in the lapatinib-resistant/lapatinib + trastuzumab–resistant models. Overexpression of constitutively active YAP rescued Survivin and phosphorylated-S6 levels, despite blockade of the MVA. These results suggest that the MVA provides alternative signaling leading to cell survival and resistance by activating YAP/TAZ–mTORC1–Survivin signaling when HER2 is blocked, suggesting novel therapeutic targets. MVA inhibitors including lipophilic statins and N-bisphosphonates may circumvent resistance to anti-HER2 therapy warranting further clinical investigation. Implications: The MVA was found to constitute an escape mechanism of survival and growth in HER2+ breast cancer models resistant to anti-HER2 therapies. MVA inhibitors such as simvastatin and zoledronic acid are potential therapeutic agents to resensitize the tumors that depend on the MVA to progress on anti-HER2 therapies.

Published
2019

49. Exome Sequencing of Cell-Free DNA from Metastatic Cancer Patients Identifies Clinically Actionable Mutations Distinct from Primary Disease.

Author

Timothy M Butler, Katherine Johnson-Camacho, Myron Peto, Nicholas J Wang, Tara A Macey, James E Korkola, Theresa M Koppie, Christopher L Corless, Joe W Gray, and Paul T Spellman

Subjects
Medicine, Science
Abstract

The identification of the molecular drivers of cancer by sequencing is the backbone of precision medicine and the basis of personalized therapy; however, biopsies of primary tumors provide only a snapshot of the evolution of the disease and may miss potential therapeutic targets, especially in the metastatic setting. A liquid biopsy, in the form of cell-free DNA (cfDNA) sequencing, has the potential to capture the inter- and intra-tumoral heterogeneity present in metastatic disease, and, through serial blood draws, track the evolution of the tumor genome. In order to determine the clinical utility of cfDNA sequencing we performed whole-exome sequencing on cfDNA and tumor DNA from two patients with metastatic disease; only minor modifications to our sequencing and analysis pipelines were required for sequencing and mutation calling of cfDNA. The first patient had metastatic sarcoma and 47 of 48 mutations present in the primary tumor were also found in the cell-free DNA. The second patient had metastatic breast cancer and sequencing identified an ESR1 mutation in the cfDNA and metastatic site, but not in the primary tumor. This likely explains tumor progression on Anastrozole. Significant heterogeneity between the primary and metastatic tumors, with cfDNA reflecting the metastases, suggested separation from the primary lesion early in tumor evolution. This is best illustrated by an activating PIK3CA mutation (H1047R) which was clonal in the primary tumor, but completely absent from either the metastasis or cfDNA. Here we show that cfDNA sequencing supplies clinically actionable information with minimal risks compared to metastatic biopsies. This study demonstrates the utility of whole-exome sequencing of cell-free DNA from patients with metastatic disease. cfDNA sequencing identified an ESR1 mutation, potentially explaining a patient's resistance to aromatase inhibition, and gave insight into how metastatic lesions differ from the primary tumor.

Published
2015
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