Single Copies of Mutant KRAS and Mutant PIK3CA Cooperate in Immortalized Human Epithelial Cells to Induce Tumor Formation
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Abstract
The selective pressures leading to cancers with mutations in both KRAS and PIK3CA are unclear. Here, we show that somatic cell knockin of both KRAS G12V and oncogenic PIK3CA mutations in human breast epithelial cells results in cooperative activation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in vitro, and leads to tumor formation in immunocompromised mice. Xenografts from double-knockin cells retain single copies of mutant KRAS and PIK3CA, suggesting that tumor formation does not require increased copy number of either oncogene, and these results were also observed in human colorectal cancer specimens. Mechanistically, the cooperativity between mutant KRAS and PIK3CA is mediated in part by Ras/p110α binding, as inactivating point mutations within the Ras-binding domain of PIK3CA significantly abates pathway signaling. In addition, Pdk1 activation of the downstream effector p90RSK is also increased by the combined presence of mutant KRAS and PIK3CA. These results provide new insights into mutant KRAS function and its role in carcinogenesis. Cancer Res; 73(11); 3248–61. ©2013 AACR.
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Several KRAS alleles had reduced comutation with NRAS and BRAF, and increased comutation with APC and PIK3CA.
“Several KRAS alleles had reduced comutation with NRAS and BRAF, and increased comutation with APC and PIK3CA”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [46]
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Cites
Site-directed mutagenesis by overlap extension using the polymerase chain reaction
Ho, S. N., Hunt, H. D., Horton, R. M., Pullen, J. K., & Pease, L. R. (1989) · Gene · doi:10.1016/0378-1119(89)90358-2 · Cited by 7,354 · see citing works
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,178 · cited 1× · see citing works
“For example, although overexpression of mutant RAS can contribute to tumorigenesis in human epithelial cells (2), overexpression of mutant RAS also has been shown to result in oncogene induced senescence in human fibroblasts (3).”
mTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt
O'Reilly, K. E., Rojo, F., She, Q.-B., Solit, D., Mills, G. B., Smith, D., Lane, H., Hofmann, F., Hicklin, D. J., Ludwig, D. L., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2925 · Cited by 2,561 · see citing works
Debnath, J., Muthuswamy, S. K., & Brugge, J. S. (2003) · Methods · doi:10.1016/s1046-2023(03)00032-x · Cited by 2,001 · see citing works
Soule, H. D., Maloney, T., Wolman, S. R., Peterson, W., Brenz, R., McGrath, C. M., Russo, J., Pauley, R. J., Jones, R. F., & Brooks, S. C. (1990) · PubMed · Cited by 1,527 · see citing works
The nuts and bolts of AGC protein kinases
Pearce, L. R., Komander, D., & Alessi, D. R. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2822 · Cited by 1,294 · see citing works
Somatic activation of the K-ras oncogene causes early onset lung cancer in mice
Johnson, L., Mercer, K., Greenbaum, D., Bronson, R. T., Crowley, D., Tuveson, D. A., & Jacks, T. (2001) · Nature · doi:10.1038/35074129 · Cited by 1,179 · see citing works
PETERSEN, O. W., Rønnov‐Jessen, L., Howlett, A. R., & Bissell, M. J. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.19.9064 · Cited by 1,096 · see citing works
Mutant PIK3CA promotes cell growth and invasion of human cancer cells.
Samuels, Y., Diaz, L. A., Schmidt-Kittler, O., Cummins, J. M., DeLong, L., Cheong, I., Rago, C., Huso, D. L., Lengauer, C., Kinzler, K. W., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.05.014 · Cited by 915 · see citing works
Glucose Deprivation Contributes to the Development of <i>KRAS</i> Pathway Mutations in Tumor Cells
Yun, J., Rago, C., Cheong, I., Pagliarini, R., Angenendt, P., Rajagopalan, H., Schmidt, K., Willson, J. K. V., Markowitz, S., Zhou, S., et al. (2009) · Science · doi:10.1126/science.1174229 · Cited by 914 · see citing works
Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells
Elenbaas, B., Spirio, L., Koerner, F., Fleming, M. D., Zimonjic, D. B., Donaher, J. L., Popescu, N. C., Hahn, W. C., & Weinberg, R. A. (2001) · Genes & Development · doi:10.1101/gad.828901 · Cited by 878 · see citing works
Sun, S., Rosenberg, L. M., Wang, X., Zhou, Z., Yue, P., Fu, H., & Khuri, F. R. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0917 · Cited by 800 · see citing works
De Roock, W., Jonker, D. J., Di Nicolantonio, F., Sartore-Bianchi, A., Tu, D., Siena, S., Lamba, S., Arena, S., Frattini, M., Piessevaux, H., et al. (2010) · JAMA · doi:10.1001/jama.2010.1535 · Cited by 748 · see citing works
Altered Growth of Human Colon Cancer Cell Lines Disrupted at Activated Ki- ras
Shirasawa, S., Furuse, M., Yokoyama, N., & Sasazuki, T. (1993) · Science · doi:10.1126/science.8465203 · Cited by 621 · see citing works
Class I PI3K in oncogenic cellular transformation
Zhao, L., & Vogt, P. K. (2008) · Oncogene · doi:10.1038/onc.2008.244 · Cited by 598 · see citing works
Binding of Ras to Phosphoinositide 3-Kinase p110α Is Required for Ras- Driven Tumorigenesis in Mice
Gupta, S., Ramjaun, A. R., Haiko, P., Wang, Y., Warne, P. H., Nicke, B., Nye, E. L., Stamp, G., Alitalo, K. K., & Downward, J. (2007) · Cell · doi:10.1016/j.cell.2007.03.051 · Cited by 589 · see citing works
KRAS Mutations in Non-Small Cell Lung Cancer
Riely, G. J., Marks, J., & Pao, W. (2009) · Proceedings of the American Thoracic Society · doi:10.1513/pats.200809-107lc · Cited by 550 · see citing works
Breast Cancer–Associated PIK3CA Mutations Are Oncogenic in Mammary Epithelial Cells
Isakoff, S. J., Engelman, J. A., Irie, H. Y., Luo, J., Brachmann, S. M., Pearline, R. V., Cantley, L. C., & Brugge, J. S. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-2612 · Cited by 505 · see citing works
Zhao, L., & Vogt, P. K. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0712169105 · Cited by 438 · see citing works
Eser, S., Reiff, N., Messer, M., Seidler, B., Gottschalk, K., Dobler, M., Hieber, M., Arbeiter, A., Klein, S., Kong, B., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.01.023 · Cited by 360 · see citing works
Nicolantonio, F. D., Arena, S., Tabernero, J. M., Grosso, S., Molinari, F., Macarulla, T. M., Russo, M., Cancelliere, C., Zecchin, D., Mazzucchelli, L., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci37539 · Cited by 343 · see citing works
Soh, J., Okumura, N., Lockwood, W. W., Yamamoto, H., Shigematsu, H., Zhang, W., Chari, R., Shames, D. S., Tang, X., MacAulay, C. E., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007464 · Cited by 227 · see citing works
Kennedy, A. L., Morton, J. P., Manoharan, I., Nelson, D. M., Jamieson, N. B., Pawlikowski, J. S., McBryan, T., Doyle, B., McKay, C., Oien, K. A., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.02.020 · Cited by 213 · see citing works
Knockin of mutant PIK3CA activates multiple oncogenic pathways
Gustin, J. P., Karakas, B., Weiss, M. B., Abukhdeir, A. M., Lauring, J. D., Garay, J. P., Cosgrove, D., Tamaki, A., Konishi, H., Konishi, Y., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0813351106 · Cited by 171 · see citing works
Self-citationHalilovic, E., She, Q.-B., Ye, Q., Pagliarini, R., Sellers, W. R., Solit, D. B., & Rosen, N. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0409 · Cited by 168 · see citing works
Kadota, M., Yang, H. H., Gomez, B. P., Sato, M., Clifford, R., Meerzaman, D. M., Dunn, B. K., Wakefield, L. M., & Lee, M. P. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009201 · Cited by 161 · see citing works
Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1
Najafov, A., Sommer, E. M., Axten, J. M., DeYoung, M. P., & Alessi, D. R. (2010) · Biochemical Journal · doi:10.1042/bj20101732 · Cited by 134 · see citing works
High prevalence of PIK3CA/AKT pathway mutations in papillary neoplasms of the breast
Troxell, M. L., Levine, J., Beadling, C., Warrick, A., Dunlap, J. B., Presnell, A., Patterson, J., Shukla, A., Olson, N., Heinrich, M. C., et al. (2009) · Modern Pathology · doi:10.1038/modpathol.2009.142 · Cited by 116 · see citing works
Konishi, H., Karakas, B., Abukhdeir, A. M., Lauring, J. D., Gustin, J. P., Garay, J. P., Konishi, Y., Gallmeier, E., Bachman, K. E., & Park, B. H. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0108 · Cited by 90 · see citing works
Self-citationCarón, R. W., Yacoub, A., Li, M., Zhu, X., Mitchell, C., Hong, Y. K., Hawkins, W., Sasazuki, T., Shirasawa, S., Kozikowski, A. P., et al. (2005) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.257.4.2 · Cited by 85 · see citing works
Technologically advanced cancer modeling in mice
Tuveson, D. A. (2002) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(01)00272-6 · Cited by 80 · see citing works
Loss of oncogenic ras expression does not correlate with loss of tumorigenicity in human cells.
Plattner, R., Anderson, M. J. M., Sato, K. Y., Fasching, C. L., Der, C. J., & Stanbridge, E. J. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.13.6665 · Cited by 80 · see citing works
Ras and Phosphoinositide 3-Kinase: Partners in Development and Tumorigenesis
Ramjaun, A. R., & Downward, J. (2007) · Cell Cycle · doi:10.4161/cc.6.23.4996 · Cited by 72 · see citing works
Lauring, J. D., Cosgrove, D., Fontana, S. C., Gustin, J. P., Konishi, H., Abukhdeir, A. M., Garay, J. P., Mohseni, M., Wang, G., Higgins, M. J., et al. (2010) · Oncogene · doi:10.1038/onc.2009.516 · Cited by 59 · see citing works
Self-citationTissue-specific p19 Arf regulation dictates the response to oncogenic K-ras
Young, N. P., & Jacks, T. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1004796107 · Cited by 59 · see citing works
Weiss, M. B., Vitolo, M. I., Mohseni, M., Rosen, D. M., Denmeade, S. R., Park, B. H., Weber, D. J., & Bachman, K. E. (2010) · Oncogene · doi:10.1038/onc.2010.220 · Cited by 56 · see citing works
Self-citationp21 (WAF1/CIP1) Mediates the Growth Response to TGF-b in Human Epithelial Cells
Bachman, K. E., Blair, B. G., BRENNER, K. R., et al. (2004) · Cancer Biology & Therapy · doi:10.4161/cbt.3.2.666 · Cited by 45 · see citing works
Self-citationArena, S., Isella, C., Martini, M., de Marco, A., Médico, E., & Bardelli, A. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1126 · Cited by 33 · see citing works
Konishi, H., Lauring, J. D., Garay, J. P., et al. (2007) · Nature Protocols · doi:10.1038/nprot.2007.409 · Cited by 24 · see citing works
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- [19]Isakoff SJ Engelman JA Irie HY Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells Cancer Res 2005 65 10992 1000 16322248
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The origins and genetic interactions of KRAS mutations are allele- and tissue-specific
Cook, J. H., Melloni, G. E. M., Gulhan, D. C., Park, P. J., & Haigis, K. M. (2021) · Nature Communications · doi:10.1038/s41467-021-22125-z · Cited by 208 · see citing works
Koustas, E., Karamouzis, M. V., Mihailidou, C., Schizas, D., & Papavassiliou, A. G. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.03.023 · Cited by 79 · see citing works
- Authors
- Wang, G. M., Wong, H. Y., Konishi, H., Blair, B. G., Abukhdeir, A. M., Gustin, J. P., Rosen, D. M., Denmeade, S. R., Rasheed, Z., Matsui, W., Garay, J. P., Mohseni, M., Higgins, M. J., Cidado, J., Jelovac, D., Croessmann, S., Cochran, R. L., Karnan, S., Konishi, Y., Ota, A., Hosokawa, Y., Argani, P., Lauring, J., & Park, B. H.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Park, Ben Ho
- ORCID
- Venue
- Cancer Research
- Published
- 2013-05-30
- Volume
- 73
- Issue
- 11
- Pages
- 3248-3261
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3674106
- OpenAlex
- W2145745448
- Cited by
- 39
- References
- 39
- Citations by year
- 2025: 2 · 2023: 1 · 2022: 3 · 2021: 1 · 2019: 7 · 2018: 2 · 2017: 4 · 2016: 5 · 2015: 5 · 2014: 7 · 2013: 2
- FWCI
- 2.83
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Japan Society for the Promotion of Science (25640107, 25460395)
- National Cancer Institute (CA088843, R01CA150142, F31CA168180, CA109274, R01CA109274, P50CA088843, CA009071, R55CA109274, T32CA009071)
- National Institute of General Medical Sciences (T32GM007309, T32GM007814, GM007309)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- KRAS G12V, PIK3CA mutation, oncogene cooperation, PI3K signaling, MAPK signaling, breast epithelial cells, colorectal cancer, Ras-binding domain, PDK1, p90RSK, tumor formation, carcinogenesis, xenografts
- MeSH terms
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Animals, Breast Neoplasms, Cell Transformation, Neoplastic, Epithelial Cells, Female, Humans, Mice, Nude, Phosphorylation, Proto-Oncogene Proteins, Biomarkers, Tumor, Proto-Oncogene Proteins p21(ras), Immunocompromised Host, Protein Serine-Threonine Kinases, Point Mutation, ras Proteins, Phosphatidylinositol 3-Kinases, MAP Kinase Signaling System, Ribosomal Protein S6 Kinases, 90-kDa, Ribosomal Protein S6 Kinases, 70-kDa, Cell Growth Processes, Mice, Gene Knock-In Techniques, Class I Phosphatidylinositol 3-Kinases, Heterografts
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