PI3K/AKT/mTOR: role in breast cancer progression, drug resistance, and treatment

Guerrero-Zotano, Ángel; Mayer, Ingrid A.; Arteaga, Carlos L.

doi:10.1007/s10555-016-9637-x

Cited by 324 publications

(287 citation statements)

References 76 publications

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“…All tsRNAs considered are significantly differentially expressed (P < 0.05). (19), PDGF signaling (20,21), sphingosine-1-phosphate (S1P) signaling (22), and mTOR signaling (23)(24)(25)(26). In addition, we observed an inhibition of the tumor suppressor PTEN signaling (27)(28)(29) and ceramide signaling (30).…”

Section: Resultsmentioning

confidence: 76%

tsRNA signatures in cancer

Balatti

Nigita

Veneziano

et al. 2017

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

223

262

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Small, noncoding RNAs are short untranslated RNA molecules, some of which have been associated with cancer development. Recently we showed that a class of small RNAs generated during the maturation process of tRNAs (tRNA-derived small RNAs, hereafter "tsRNAs") is dysregulated in cancer. Specifically, we uncovered tsRNA signatures in chronic lymphocytic leukemia and lung cancer and demonstrated that the ts-4521/3676 cluster (now called "ts-101" and "ts-53," respectively), ts-46, and ts-47 are down-regulated in these malignancies. Furthermore, we showed that tsRNAs are similar to Piwi-interacting RNAs (piRNAs) and demonstrated that ts-101 and ts-53 can associate with PiwiL2, a protein involved in the silencing of transposons. In this study, we extended our investigation on tsRNA signatures to samples collected from patients with colon, breast, or ovarian cancer and cell lines harboring specific oncogenic mutations and representing different stages of cancer progression. We detected tsRNA signatures in all patient samples and determined that tsRNA expression is altered upon oncogene activation and during cancer staging. In addition, we generated a knockedout cell model for ts-101 and ts-46 in HEK-293 cells and found significant differences in gene-expression patterns, with activation of genes involved in cell survival and down-regulation of genes involved in apoptosis and chromatin structure. Finally, we overexpressed ts-46 and ts-47 in two lung cancer cell lines and performed a clonogenic assay to examine their role in cell proliferation. We observed a strong inhibition of colony formation in cells overexpressing these tsRNAs compared with untreated cells, confirming that tsRNAs affect cell growth and survival.tsRNA | tRF | tDR | ncRNA | tRNA fragments

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Section: Resultsmentioning

confidence: 76%

tsRNA signatures in cancer

Balatti

Nigita

Veneziano

et al. 2017

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

223

262

View full text Add to dashboard Cite

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“…It has also been reported that p63 can activate the Jagged 1/notch pathway [Ma et al, ]; and Jagged 1/notch can regulate the physiological activity of the cells through PI3K/AKT, MAPK, and Wnt pathway [Xiao et al, ]. Besides, according to previous studies, PI3K/AKT plays an important role in tumor cell proliferation and metastasis in many kinds of cancers [Guerrero‐Zotano et al, ; Mayer and Arteaga, ]. Furthermore, miR‐184 exerts its function through different pathways, including AKT pathway to regulate cancer proliferation and invasion [Foley et al, ; Feng and Dong, ].…”

Section: Discussionmentioning

confidence: 98%

MicroRNA-184 Modulates Human Central Nervous System Lymphoma Cells Growth and Invasion by Targeting iASPP

Liang

Wei

et al. 2017

J. Cell. Biochem.

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Central nervous system lymphoma (CNSL) remains a diagnostical and therapeutical challenge. MiRNAs post-transcriptionally regulate expression of targeted mRNAs through binding to their 3' UTR to inhibit their translation or promote their degradation. Oncoprotein inhibitory member of the ASPP family (iASPP), a key inhibitor of tumor suppressor p53, has been reported to play oncogenic role in cancers. Our present study was aimed to determine whether the miR-184/iASPP axis is involved in the proliferation and invasion of CNSL. A reduced level of miR-184 was observed in CNSL tissues. Exogenous miR-184 inhibited cell survival and invasion, as well as the tumor volumes, while miR-184 inhibition could reverse this process. The RNA and protein levels of iASPP were significantly inhibited by miR-184, and the 3' UTR of iASPP was shown to be a target of miR-184. The expression of iASPP was up-regulated in CNSL tissues, compared to that of the normal brain tissues. The inhibition of iASPP by shRNA iASPP significantly repressed CNSL cells' proliferation and invasion, and reduced the volume of the tumor. Besides, iASPP overexpression could partly restore the suppressive effect of miR-184 on CNSL cell proliferation and invasive capability. We also revealed that miR-184/iASPP axis regulated the proliferation and invasion via PI3K/Akt signaling pathway, which presents a novel potential therapy for intervention of CNSL. Taken together, our findings revealed the detailed role of the miR-184/iASPP axis in CNSL and this axis might modulate the proliferation and invasion of CNSL via regulating the PI3K/Akt signaling pathway. J. Cell. Biochem. 118: 2645-2653, 2017. © 2017 Wiley Periodicals, Inc.

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“…As PI3K signaling is one of the most hyperactive signaling pathways in breast cancer, targeting this pathway appears to be a promising therapeutic strategy (Cidado and Park, ; Pal and Mandal, ). However, some trials have shown that the use of PI3K inhibitors as a treatment for breast cancer is likely to be limited due to the development of acquired resistance in patients (Guerrero‐Zotano et al, ; Le et al, ). In this study, we found that inhibition of PI3K using LY294002 could stimulate β‐catenin expression in human breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Suppression of epidermal growth factor receptor‐mediated β‐catenin nuclear accumulation enhances the anti‐tumor activity of phosphoinositide 3‐kinase inhibitor in breast cancer

Niu

Wang

Liang

et al. 2019

Cell Biology International

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Phosphoinositide 3‐kinase (PI3K) signaling is frequently deregulated in breast cancer and plays a critical role in tumor progression. However, resistance to PI3K inhibitors in breast cancer has emerged, which is due to the enhanced β‐catenin nuclear accumulation. Until now, the mechanisms underlying PI3K inhibition‐induced β‐catenin nuclear accumulation remains largely unknown. In the present study, we found inhibition of PI3K with LY294002 promoted β‐catenin nuclear accumulation in MCF‐7 and MDA‐MB‐231 breast cancer cells. Combining PI3K inhibitor LY294002 with XAV‐939, an inhibitor against β‐catenin nuclear accumulation, produced an additive anti‐proliferation effect against breast cancer cells. Subsequent experiments suggested β‐catenin nuclear accumulation induced by PI3K inhibition depended on the feedback activation of epidermal growth factor receptor (EGFR) signaling pathway in breast cancer cells. Inhibition of EGFR phosphorylation with Gefitinib enhanced anti‐proliferation effect of PI3K inhibitor LY294002 in MCF‐7 and MDA‐MB‐231 cells. Taken together, our findings may elucidate a possible mechanism explaining the poor outcome of PI3K inhibitors in breast cancer treatment.

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PI3K/AKT/mTOR: role in breast cancer progression, drug resistance, and treatment

Cited by 324 publications

References 76 publications

tsRNA signatures in cancer

tsRNA signatures in cancer

MicroRNA-184 Modulates Human Central Nervous System Lymphoma Cells Growth and Invasion by Targeting iASPP

Suppression of epidermal growth factor receptor‐mediated β‐catenin nuclear accumulation enhances the anti‐tumor activity of phosphoinositide 3‐kinase inhibitor in breast cancer

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