Signaling pathway switch in breast cancer
© Guille et al.; licensee BioMed Central Ltd. 2013
Received: 14 May 2013
Accepted: 20 June 2013
Published: 27 June 2013
Next generation sequencing studies have drawn the general landscape of breast cancers and identified hundreds of new, actual therapeutic targets. Two major signaling pathways seem to be altered in a vast proportion of breast cancers. The PI3 kinase/AKT pathway is activated and the JUN/MAPK pathway is repressed. Via the regulation of the cell cycle this metabolic switch impacts on the balance between self-renewal, proliferation and differentiation of the tumor-initiating cells
Recent results from next generation sequencing (NGS) studies have established the repertoire of driver gene mutations and copy number alterations (CNA) in breast cancer [1–4]. Nearly 900 cancers representative of all major expression subtypes (basal, luminal A and B, ERBB2 and normal-like) have been studied. Many recurrent mutations have been uncovered. Mutations in TP53, PIK3CA, GATA3 and PTEN genes are among the most frequent. These studies have forever changed our understanding of mammary oncogenesis.
Many studies will extend these pioneering ones but it is already possible to speculate further on the NGS data. Data analysis revealed that some alterations (CNA and/or mutations) never occur in the same tumor, i.e. are mutually exclusive [1–4]. Two main signaling pathways seem to be targeted, the PI3K/AKT pathway and the JUN/MAPK pathway [1–4]. Alterations in components of the PI3K/AKT pathway (PIK3CA, PIK3R1, AKTs, PTEN, INPP4B…) are mutually exclusive but strikingly, amplification and upregulation of genes encoding receptor-type tyrosine kinases (RTKs) (IGF1R, EGFR, ERBB2) are also (globally) mutually exclusive with alterations of the PI3K/AKT pathway. This suggests that the primary role of RTK amplification or mutation is to activate the PI3K/AKT pathway. Thus, in the normal mammary epithelium these RTKs are repressed or expressed at a low level and their signaling is primarily oriented toward the JUN/MAPK pathway, whereas when upregulated in tumor cells they stimulate the PI3K/AKT pathway. To obtain this dosage effect could be the reason for the amplification of ERBB2 and FGFR1 genes, although there could be other reasons . It is known that the PI3K/AKT pathway is activated in tumors with mutated EGFR or overexpression of ERBB2 and determines the response to ERBB targeted inhibitors . Within the JUN/MAPK pathway alterations of the components are also mutually exclusive . Components of the JUN/MAPK pathway are inactivated by deletions and mutations, such as MAP2K4 and MAP3K1, or by amplifications, such as PAK1. Most importantly, alterations leading to the activation of the PI3K/AKT pathway and those leading to the inactivation of the JUN/MAPK pathway are mutually exclusive . Finally, not only mutations and genomic rearrangements affect genes encoding components of the two pathways but opposite modifications in expression patterns of these genes could also participate to their switch in breast cancer.
Our hypothesis is that one important consequence of mutations, CNA and modifications of expression is to shift cell signaling in the targeted mammary epithelial cell from an active “JUN/MAPK pathway – inactive PI3K/AKT pathway” state to an active “PI3K/AKT pathway – inactive JUN/MAPK pathway” state.
Testing the hypothesis
A second major effect of PI3K/AKT pathway activation and JUN/MAPK inhibition is on the metabolism of the tumor-initiating cells. The latter are particularly resistant to oxidative processes and ROS production. The PI3K/AKT pathway, beside its role on cell growth and survival, regulates a number of metabolic processes including cell glucose uptake and neoglucogenesis in relation with nutrient availability and redox and energy conditions. It plays an important role in the glycolytic phenotype of tumors . Forkhead transcription factors FOXO are downstream of the PI3K/AKT and JUN/MAPK cascades. FOXOs play a major role in the regulation of both the cell cycle and metabolism . They prevent stem cells to accumulate ROS and allow DNA repair or quiescence. FOXOs are activated by the JUN kinase signaling pathway in the presence of oxidative stress. Conversely, activation of the PI3K/AKT and inhibition of JUN/MAPK pathways overrules the tumor suppressive effect of FOXOs and allows G1 progression. With respect to cell cycle and cell fate decisions FOXO transcription factors could thus represent important integrators of the two signaling pathways that are predominantly altered in breast cancer. They are therefore important targets in mammary oncogenesis. FOXO genes have not been found among the most frequently altered genes in breast cancer in NGS studies [1–4]; they are probably not directly targeted (yet, we have recently found rare mutations and deletions of the FOXO3 gene; Cornen et al., submitted). FOXOs functions may also be modified but maintained to ensure some degree of metabolic regulation in the tumor-initiating cells. FOXOs and P53 act on the same cellular processes and transcription programs, and are intimately cross-regulated .
Implications of the hypothesis
The NGS studies have drawn the general landscape of breast cancers and identified hundreds of new, actual targets. Although the role of many of them needs clarification, especially regarding the transcription factors (e.g. GATA3, RUNX, NCORs…), two major signaling pathways seem to be altered. This is good news since strategies to counter the consequences of pathway alterations are known and could be improved. Inhibiting the PI3K/AKT pathway appears as a paramount strategy to stop tumor growth . If it fails one could adopt a strategy that takes into account both the PI3K/AKT and JUN/MAPK pathways but because they are truly interrelated this may not be helpful. Targeting additional alterations or pathways (including synthetic lethal ones)  outside the PI3K/AKT and JUN/MAPK pathways could be more successful.
Studies on breast cancer in our laboratory are supported by Inserm, Institut Paoli-Calmettes, Ligue Nationale Contre le Cancer (Label DB) and Institut National du Cancer (ACI2007, AO2008, IVOIRES, and INCa-DGOS-Inserm 6038)
- The Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature. 2012, 490: 61-70. 10.1038/nature11412.PubMed CentralView ArticleGoogle Scholar
- Shah P, Roth A, Goya R, Oloumi A, Ha G, Zhao Y: The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012, 486: 385-399.Google Scholar
- Banerji S, Cibulskis K, Rangel-Escareno K, Brown KK, Carter SL, Frederick AM: Sequence analysis of mutations and translocations across breast cancer subtypes. Nature. 2012, 486: 405-409. 10.1038/nature11154.PubMed CentralView ArticlePubMedGoogle Scholar
- Ellis MJ, Ding L, Shen D, Luo J, Suman VJ, Wallis JW: Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature. 2012, 486: 353-360.PubMed CentralPubMedGoogle Scholar
- Birnbaum D, Sircoulomb F, Imbert J: A reason why the ERBB2 gene is amplified and not mutated in breast cancer. Cancer Cell Int. 2009, 9: 5-10.1186/1475-2867-9-5.PubMed CentralView ArticlePubMedGoogle Scholar
- Hynes N, MacDonald G: ErbB receptors and signaling pathways in cancer. Curr Op Cell Biol. 2009, 21: 177-184. 10.1016/j.ceb.2008.12.010.View ArticlePubMedGoogle Scholar
- Wu G, Feng X, Lincoln Stein L: A human functional protein interaction network and its application to cancer data analysis. Genome Biol. 2010, 11: R53-10.1186/gb-2010-11-5-r53.PubMed CentralView ArticlePubMedGoogle Scholar
- Oxford KW, Scadden DT: Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat Rev Genet. 2008, 9: 115-127. 10.1038/nrg2269.View ArticleGoogle Scholar
- Burdon T, Smith A, Savatier P: Signalling, cell cycle and pluripotency in embryonic stem cells. Trends Cell Biol. 2002, 12: 432-438. 10.1016/S0962-8924(02)02352-8.View ArticlePubMedGoogle Scholar
- Cairns RA, Harris IS, Mak TW: Regulation of cancer metabolism. Nat Rev Cancer. 2011, 11: 85-95.View ArticlePubMedGoogle Scholar
- Eijkelenboom A, Burgering BMT: FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol. 2013, 14: 83-97.View ArticlePubMedGoogle Scholar
- Grunt TW, Mariani GL: Novel approaches for molecular targeted therapy of breast cancer: interfering with PI3K/AKT/mTOR signaling. Curr Cancer Drug Targets. 2013, 13: 188-204. 10.2174/1568009611313020008.View ArticlePubMedGoogle Scholar
- Eisinger F, Sobol H, Birnbaum D: Hypothesis: more mutations to cure cancer?. Oncol Rep. 1999, 6: 1189-1190.PubMedGoogle Scholar
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