Pathway-Centric Integrative Analysis Identifies RRM2 as a Prognostic Marker in Breast Cancer Associated with Poor Survival and Tamoxifen Resistance
Breast cancer (BCa) molecular subtypes include luminal A, luminal B, normal-like, HER-2–enriched, and basal-like tumors, among which luminal B and basal-like cancers are highly aggressive. Biochemical pathways associated with patient survival or treatment response in these more aggressive subtypes a...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2014-05-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S147655861400061X |
| _version_ | 1828295179181752320 |
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| author | Nagireddy Putluri Suman Maity Ramakrishna Kommagani Chad J. Creighton Vasanta Putluri Fengju Chen Sarmishta Nanda Salil Kumar Bhowmik Atsushi Terunuma Tiffany Dorsey Agostina Nardone Xiaoyong Fu Chad Shaw Tapasree Roy Sarkar Rachel Schiff John P. Lydon Bert W. O’Malley Stefan Ambs Gokul M. Das George Michailidis Arun Sreekumar |
| author_facet | Nagireddy Putluri Suman Maity Ramakrishna Kommagani Chad J. Creighton Vasanta Putluri Fengju Chen Sarmishta Nanda Salil Kumar Bhowmik Atsushi Terunuma Tiffany Dorsey Agostina Nardone Xiaoyong Fu Chad Shaw Tapasree Roy Sarkar Rachel Schiff John P. Lydon Bert W. O’Malley Stefan Ambs Gokul M. Das George Michailidis Arun Sreekumar |
| author_sort | Nagireddy Putluri |
| collection | DOAJ |
| description | Breast cancer (BCa) molecular subtypes include luminal A, luminal B, normal-like, HER-2–enriched, and basal-like tumors, among which luminal B and basal-like cancers are highly aggressive. Biochemical pathways associated with patient survival or treatment response in these more aggressive subtypes are not well understood. With the limited availability of pathologically verified clinical specimens, cell line models are routinely used for pathway-centric studies. We measured the metabolome of luminal and basal-like BCa cell lines using mass spectrometry, linked metabolites to biochemical pathways using Gene Set Analysis, and developed a novel rank-based method to select pathways on the basis of their enrichment in patient-derived omics data sets and prognostic relevance. Key mediators of the pathway were then characterized for their role in disease progression. Pyrimidine metabolism was altered in luminal versus basal BCa, whereas the combined expression of its associated genes or expression of one key gene, ribonucleotide reductase subunit M2 (RRM2) alone, associated significantly with decreased survival across all BCa subtypes, as well as in luminal patients resistant to tamoxifen. Increased RRM2 expression in tamoxifen-resistant patients was verified using tissue microarrays, whereas the metabolic products of RRM2 were higher in tamoxifen-resistant cells and in xenograft tumors. Both genetic and pharmacological inhibition of this key enzyme in tamoxifen-resistant cells significantly decreased proliferation, reduced expression of cell cycle genes, and sensitized the cells to tamoxifen treatment. Our study suggests for evaluating RRM2-associated metabolites as noninvasive markers for tamoxifen resistance and its pharmacological inhibition as a novel approach to overcome tamoxifen resistance in BCa. |
| first_indexed | 2024-04-13T11:50:39Z |
| format | Article |
| id | doaj.art-73ffcf9c2f0a43e69ef35d2b0b955497 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 |
| language | English |
| last_indexed | 2024-04-13T11:50:39Z |
| publishDate | 2014-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-73ffcf9c2f0a43e69ef35d2b0b9554972022-12-22T02:48:04ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862014-05-0116539040210.1016/j.neo.2014.05.007Pathway-Centric Integrative Analysis Identifies RRM2 as a Prognostic Marker in Breast Cancer Associated with Poor Survival and Tamoxifen ResistanceNagireddy Putluri0Suman Maity1Ramakrishna Kommagani2Chad J. Creighton3Vasanta Putluri4Fengju Chen5Sarmishta Nanda6Salil Kumar Bhowmik7Atsushi Terunuma8Tiffany Dorsey9Agostina Nardone10Xiaoyong Fu11Chad Shaw12Tapasree Roy Sarkar13Rachel Schiff14John P. Lydon15Bert W. O’Malley16Stefan Ambs17Gokul M. Das18George Michailidis19Arun Sreekumar20Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USADepartment of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USADepartment of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USADepartment of Medicine, Baylor College of Medicine, Houston, TX, USADepartment of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USADepartment of Medicine, Baylor College of Medicine, Houston, TX, USALester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USADepartment of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USALaboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USALaboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USALester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USALester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USADepartment of Medicine, Baylor College of Medicine, Houston, TX, USADepartment of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USADepartment of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USADepartment of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USALaboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USADepartment of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USADepartment of Statistics, University of Michigan, Ann Arbor, MI, USADepartment of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USABreast cancer (BCa) molecular subtypes include luminal A, luminal B, normal-like, HER-2–enriched, and basal-like tumors, among which luminal B and basal-like cancers are highly aggressive. Biochemical pathways associated with patient survival or treatment response in these more aggressive subtypes are not well understood. With the limited availability of pathologically verified clinical specimens, cell line models are routinely used for pathway-centric studies. We measured the metabolome of luminal and basal-like BCa cell lines using mass spectrometry, linked metabolites to biochemical pathways using Gene Set Analysis, and developed a novel rank-based method to select pathways on the basis of their enrichment in patient-derived omics data sets and prognostic relevance. Key mediators of the pathway were then characterized for their role in disease progression. Pyrimidine metabolism was altered in luminal versus basal BCa, whereas the combined expression of its associated genes or expression of one key gene, ribonucleotide reductase subunit M2 (RRM2) alone, associated significantly with decreased survival across all BCa subtypes, as well as in luminal patients resistant to tamoxifen. Increased RRM2 expression in tamoxifen-resistant patients was verified using tissue microarrays, whereas the metabolic products of RRM2 were higher in tamoxifen-resistant cells and in xenograft tumors. Both genetic and pharmacological inhibition of this key enzyme in tamoxifen-resistant cells significantly decreased proliferation, reduced expression of cell cycle genes, and sensitized the cells to tamoxifen treatment. Our study suggests for evaluating RRM2-associated metabolites as noninvasive markers for tamoxifen resistance and its pharmacological inhibition as a novel approach to overcome tamoxifen resistance in BCa.http://www.sciencedirect.com/science/article/pii/S147655861400061X |
| spellingShingle | Nagireddy Putluri Suman Maity Ramakrishna Kommagani Chad J. Creighton Vasanta Putluri Fengju Chen Sarmishta Nanda Salil Kumar Bhowmik Atsushi Terunuma Tiffany Dorsey Agostina Nardone Xiaoyong Fu Chad Shaw Tapasree Roy Sarkar Rachel Schiff John P. Lydon Bert W. O’Malley Stefan Ambs Gokul M. Das George Michailidis Arun Sreekumar Pathway-Centric Integrative Analysis Identifies RRM2 as a Prognostic Marker in Breast Cancer Associated with Poor Survival and Tamoxifen Resistance Neoplasia: An International Journal for Oncology Research |
| title | Pathway-Centric Integrative Analysis Identifies RRM2 as a Prognostic Marker in Breast Cancer Associated with Poor Survival and Tamoxifen Resistance |
| title_full | Pathway-Centric Integrative Analysis Identifies RRM2 as a Prognostic Marker in Breast Cancer Associated with Poor Survival and Tamoxifen Resistance |
| title_fullStr | Pathway-Centric Integrative Analysis Identifies RRM2 as a Prognostic Marker in Breast Cancer Associated with Poor Survival and Tamoxifen Resistance |
| title_full_unstemmed | Pathway-Centric Integrative Analysis Identifies RRM2 as a Prognostic Marker in Breast Cancer Associated with Poor Survival and Tamoxifen Resistance |
| title_short | Pathway-Centric Integrative Analysis Identifies RRM2 as a Prognostic Marker in Breast Cancer Associated with Poor Survival and Tamoxifen Resistance |
| title_sort | pathway centric integrative analysis identifies rrm2 as a prognostic marker in breast cancer associated with poor survival and tamoxifen resistance |
| url | http://www.sciencedirect.com/science/article/pii/S147655861400061X |
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