The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis

Utermark, Tamara; Rao, Trisha; Cheng, Hai‐Ling Margaret; Wang, Qi; Lee, Sang Hyun; Wang, Zhigang C.; Iglehart, J. Dirk; Roberts, Thomas M.; Muller, William J.; Zhao, Jean J.

doi:10.1101/gad.191973.112

Cited by 121 publications

(132 citation statements)

References 45 publications

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“…Despite this, the R-Ras2-dependent PI3Ka pool is clearly relevant in vivo, given the marked tumorigenic and metastatic defects shown by R-Ras2-deficient breast cancer cells when implanted in recipient mice. The morphogenetic alterations seen in preneoplasic mammary glands of MMTV-Her2 tg ;Rras2 À / À mice, together with the signalling compensation events detected in tumours arising in those mice, are also indirect evidence in favour of defects in the PI3Ka/Akt/ mTORC route in this experimental model 30,31,[39][40][41][42][43][44][45] . However, as reconstitution experiments are not possible in this case, we cannot formally exclude the possibility that those events could be generated by defects in other R-Ras2-dependent signalling routes (Supplementary Discussion).…”

Section: R-ras2 Deficient Tumours Develop Compensatory Mechanismsmentioning

confidence: 65%

“…In this transgenic system, the overexpression of the wild-type Her2 receptor (also known as Neu and Erbb2) in breast epithelial cells triggers mammary gland hyperplasia and, eventually, breast cancer. Thus, it recapitulates the transforming events that take place in human Her2 þ breast tumours, a frequent PI3Ka/Akt-dependent breast cancer subtype 30,31 . To investigate the participation of R-Ras2 in this stepwise tumorigenic programme, we first analysed the structure of pre-neoplasic mammary glands in cohorts of pubertal MMTVHer2 tg ;Rras2 þ / þ and MMTV-Her2 tg ;Rras2 À / À female mice.…”

Section: R-ras2 Uses Different Downstream Effectors During Metastasismentioning

confidence: 72%

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Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

et al. 2014

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R-Ras2 is a transforming GTPase that shares downstream effectors with Ras subfamily proteins. However, little information exists about the function of this protein in tumorigenesis and its signalling overlap with classical Ras GTPases. Here we show, by combining loss-and gain-of-function studies in breast cancer cells, mammary epithelial cells and mouse models, that endogenous R-Ras2 has a role in both primary breast tumorigenesis and the late metastatic steps of cancer cells in the lung parenchyma. R-Ras2 drives tumorigenesis in a phosphatidylinostiol-3 kinase (PI3K)-dependent and signalling autonomous manner. By contrast, its prometastatic role requires other priming oncogenic signals and the engagement of several downstream elements. R-Ras2 function is required even in cancer cells exhibiting constitutive activation of classical Ras proteins, indicating that these GTPases are not functionally redundant. Our results also suggest that application of long-term R-Ras2 therapies will result in the development of compensatory mechanisms in breast tumours.

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Section: R-ras2 Deficient Tumours Develop Compensatory Mechanismsmentioning

confidence: 65%

Section: R-ras2 Uses Different Downstream Effectors During Metastasismentioning

confidence: 72%

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

et al. 2014

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“…Thus, there is considerable need to determine the isoform dependence of a given tumor class. Recent work in model systems and human tumor cell lines has shown that tumors driven by oncogenes and activated receptors such as HER2 depend on p110α, suggesting that inhibitors targeting this isoform might be efficacious in this tumor class (16). Our original work and that of others has shown that many PTEN-null tumors depend on p110β (22)(23)(24)(25)(26).…”

Section: Discussionmentioning

confidence: 85%

“…It is conceivable that the signal intensity of the p110β-dependent input is much lower than the Kras-generated signal carried by p110α. This possibility, together with the fact that p110α has a stronger kinase activity than p110β (16,39), would explain the shift toward a p110α requirement. Alternatively, it is possible that activation of Kras both activates p110α and shuts off the signal responsible for p110β activation.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, there are several cancer types that have been reported to have elevated levels and/or genomic amplifications of these other isoforms, indicating that they too may contribute to cancer (13,14). In addition, activation of receptor tyrosine kinases such as VEGF receptor, EGF receptor, PDGF receptor, or human epidermal growth factor receptor 2 (HER2) leading to the activation of the PI3K pathway usually requires p110α for signaling and tumorigenesis (15)(16)(17). Rat sarcoma (Ras) proteins, which signal in part through PI3K pathway, are also frequently mutated in human cancer (18,19).…”

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confidence: 99%

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PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context

Schmit

Utermark

Zhang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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There has been increasing interest in the use of isoform-selective inhibitors of phosphatidylinositide-3-kinase (PI3K) in cancer therapy. Using conditional deletion of the p110 catalytic isoforms of PI3K to predict sensitivity of cancer types to such inhibitors, we and others have demonstrated that tumors deficient of the phosphatase and tensin homolog (PTEN) are often dependent on the p110β isoform of PI3K. Because human cancers usually arise due to multiple genetic events, determining whether other genetic alterations might alter the p110 isoform requirements of PTEN-null tumors becomes a critical question. To investigate further the roles of p110 isoforms in PTEN-deficient tumors, we used a mouse model of ovarian endometrioid adenocarcinoma driven by concomitant activation of the rat sarcoma protein Kras, which is known to activate p110α, and loss of PTEN. In this model, ablation of p110β had no effect on tumor growth, whereas p110α ablation blocked tumor formation. Because ablation of PTEN alone is often p110β dependent, we wondered if the same held true in the ovary. Because PTEN loss alone in the ovary did not result in tumor formation, we tested PI3K isoform dependence in ovarian surface epithelium (OSE) cells deficient in both PTEN and p53. These cells were indeed p110β dependent, whereas OSEs expressing activated Kras with or without PTEN loss were p110α dependent. Furthermore, isoform-selective inhibitors showed a similar pattern of the isoform dependence in established Kras G12D /PTEN-deficient tumors. Taken together, our data suggest that, whereas in some tissues PTEN-null tumors appear to inherently depend on p110β, the p110 isoform reliance of PTEN-deficient tumors may be altered by concurrent mutations that activate p110α.ovarian cancer | PI3K inhibitors | genetically engineered mouse model

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Quantitative structure‐selectivity relationship (QSSR)‐based molecular insight into the cross‐reactivity and specificity of chemotherapeutic inhibitors between PI3Kα and PI3Kβ

Ding

Liu

Zhu

2017

Journal of Chemometrics

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Selective inhibition of phosphoinositide 3-kinase (PI3K) isoforms α and β with small-molecule inhibitors can result in distinct biological effects on anticancer chemotherapy. However, many existing PI3K inhibitors have moderate or high promiscuity and cross-reactivity between the 2 kinase isoforms. Here, a quantitative structure-selectivity relationship-based statistical modeling scheme was used to characterize the relative contribution of independent kinase residues to inhibitor selectivity and to predict the selectivity and specificity for existing PI3K inhibitors. It is found that the residue type and distribution of kinase's active site play an important role in inhibitor selectivity, while rest of the kinase may contribute to the selectivity through long-range chemical interactions and indirect allosteric effect. The selectivity is also determined by the configuration difference between PI3Kα and PI3Kβ kinase domains. Larger inhibitor compounds have lower binding potency to PI3Kβ than PI3Kα and thus possess higher selectivity for PI3Kα over PI3Kβ.KEYWORDS chemotherapeutic agent, inhibitor selectivity, phosphoinositide 3-kinase, quantitative structure-selectivity relationship, statistical modeling

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The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis

Cited by 121 publications

References 45 publications

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context

Quantitative structure‐selectivity relationship (QSSR)‐based molecular insight into the cross‐reactivity and specificity of chemotherapeutic inhibitors between PI3Kα and PI3Kβ

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