Active PI3K Pathway Causes an Invasive Phenotype Which Can Be Reversed or Promoted by Blocking the Pathway at Divergent Nodes

Wallin, Jeffrey J.; Guan, Jane; Edgar, Kyle A.; Zhou, Wei; Francis, Ross; Torres, Anthony C.; Haverty, Peter M.; Eastham-Anderson, Jeffrey; Arena, Sabrina; Bardelli, Alberto; Griffin, Sue T.; Goodall, Jane C.; Grimshaw, Kyla M.; Hoeflich, Klaus P.; Torrance, C; Belvin, Marcia; Friedman, Lori S.

doi:10.1371/journal.pone.0036402

Cited by 44 publications

(35 citation statements)

References 47 publications

(59 reference statements)

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“…Although these authors clearly demonstrated that mTORC2 is required to undergo EMT, their study argued against a major role for mTORC1 in this process, because rapamycin did not affect the TGF-b-induced EMT phenotype. However, in agreement with our findings, a pro-EMT effect of mTORC1 inhibition was suggested by a more recent study (26). Using syngenic MCF10A cell lines with an activating mutation in the PIK3CA gene, Wallin and colleagues showed that pharmacologic mTOR inhibition potentiated EMT and the invasive phenotype resulting from activation of the PI3K pathway.…”

Section: Discussionsupporting

confidence: 92%

“…mTOR stimulation results in the upregulation of metabolism and cell growth, mainly through protein and lipid syntheses (22). Recent reports have suggested a role for mTOR in the EMT process, but with conflicting results (23)(24)(25)(26). According to Gulhati and colleagues, mTORC1 and mTORC2 complexes positively regulate EMT, as well as the motility and metastastic abilities of colorectal cancer cells (23).…”

Section: Discussionmentioning

confidence: 99%

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Genetic and Pharmacologic Inhibition of mTORC1 Promotes EMT by a TGF-β–Independent Mechanism

et al. 2013

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Epithelial-to-mesenchymal transition (EMT) is a transdifferentiation process that converts epithelial cells into highly motile mesenchymal cells. This physiologic process occurs largely during embryonic development but is aberrantly reactivated in different pathologic situations, including fibrosis and cancer. We conducted a siRNA screening targeted to the human kinome with the aim of discovering new EMT effectors. With this approach, we have identified mTOR complex 1 (mTORC1), a nutrient sensor that controls protein and lipid synthesis, as a key regulator of epithelial integrity. Using a combination of RNAi and pharmacologic approaches, we report here that inhibition of either mTOR or RPTOR triggers EMT in mammary epithelial cells. This EMT was characterized by the induction of the mesenchymal markers such as fibronectin, vimentin, and PAI-1, together with the repression of epithelial markers such as E-cadherin and ZO-3. In addition, mTORC1 blockade enhanced in vivo migratory properties of mammary cells and induced EMT independent of the TGF-b pathway. Finally, among the transcription factors known to activate EMT, both ZEB1 and ZEB2 were upregulated following mTOR repression. Their increased expression correlated with a marked reduction in miR-200b and miR-200c mRNA levels, two microRNAs known to downregulate ZEB1 and ZEB2 expression. Taken together, our findings unravel a novel function for mTORC1 in maintaining the epithelial phenotype and further indicate that this effect is mediated through the opposite regulation of ZEB1/ZEB2 and miR-200b and miR-200c. Furthermore, these results suggest a plausible etiologic explanation for the progressive pulmonary fibrosis, a frequent adverse condition associated with the therapeutic use of mTOR inhibitors. Cancer Res; 73(22); 6621-31. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Genetic and Pharmacologic Inhibition of mTORC1 Promotes EMT by a TGF-β–Independent Mechanism

et al. 2013

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“…Furthermore, we found that the PIK3CA and HER2 + PIK3CA tumors displayed high expression of EMT and stem cell markers and that induction of PIK3CA promoted mammosphere formation. These data are in agreement with in vitro studies that have implicated the PI3K pathway in EMT (31,32) and stem cell maintenance in breast cancer (33)(34)(35). Therefore, the association between PIK3CA mutations and the claudin-low subtype of breast cancer, as well as EMT and stem-like features, suggests that HER2…”

Section: Her2 and Pi3ksupporting

confidence: 91%

Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies

Hanker¹,

Pfefferle²,

Balko

et al. 2013

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

176

142

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Human epidermal growth factor receptor 2 (HER2; ERBB2) amplification and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations often co-occur in breast cancer. Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to correlate with a diminished response to HER2-directed therapies. We generated a mouse model of HER2-overexpressing (HER2 H1047R-mutant breast cancer. Mice expressing both human HER2 and mutant PIK3CA in the mammary epithelium developed tumors with shorter latencies compared with mice expressing either oncogene alone. HER2 and mutant PIK3CA also cooperated to promote lung metastases. By microarray analysis, HER2-driven tumors clustered with luminal breast cancers, whereas mutant PIK3CA tumors were associated with claudin-low breast cancers. PIK3CA and HER2 + /PIK3CA tumors expressed elevated transcripts encoding markers of epithelial-tomesenchymal transition and stem cells. Cells from HER2 + /PIK3CA tumors more efficiently formed mammospheres and lung metastases. Finally, HER2 + /PIK3CA tumors were resistant to trastuzumab alone and in combination with lapatinib or pertuzumab. Both drug resistance and enhanced mammosphere formation were reversed by treatment with a PI3K inhibitor. In sum, PIK3CA H1047R accelerates HER2-mediated breast epithelial transformation and metastatic progression, alters the intrinsic phenotype of HER2-overexpressing cancers, and generates resistance to approved combinations of anti-HER2 therapies.

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“…[65] AKT hyper-activation and PIK3CA knock-in can promote EMT in various human cancers. [61][62][63][64][65][66] The association between EMT and PI3K activation has also been reported in ERα-negative endometrial carcinomas. [67] Twist overexpression has also been correlated with the induction of tumor cell invasion in GBM.…”

Section: Emt Cell Invasion and Motilitymentioning

confidence: 99%

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

Crespo¹,

Kind²,

Arcaro³

2016

JCMT

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The PI3K/AKT/mTOR (PAM) pathway is involved in a variety of cellular functions and often contributes to oncogenesis and cancer progression. It has been recognized that this pathway is frequently activated in the most common central nervous system cancers of adults and children, malignant gliomas and medulloblastomas (MB). In these tumors, the PAM network controls key functions necessary for cell invasion and metastasis, such as cell motility. This review summarizes the current knowledge about the role of PAM signaling in cell invasion and metastasis in gliomas and MB. Current approaches to inhibit cell invasion and metastasis by targeting the PAM pathway will also be discussed.

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Active PI3K Pathway Causes an Invasive Phenotype Which Can Be Reversed or Promoted by Blocking the Pathway at Divergent Nodes

Cited by 44 publications

References 47 publications

Genetic and Pharmacologic Inhibition of mTORC1 Promotes EMT by a TGF-β–Independent Mechanism

Genetic and Pharmacologic Inhibition of mTORC1 Promotes EMT by a TGF-β–Independent Mechanism

Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

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