Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1

Zhu, Jidong; Blenis, John; Yuan, Junying

doi:10.1073/pnas.0802785105

Cited by 211 publications

(173 citation statements)

References 24 publications

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“…Similar to previous findings that Akt promotes pluripotency through the regulation and/or stabilization of Oct4, Sox2 and cMyc, in this study we observed that Akt-NLS also showed increased protein levels of reprogramming factors either similar or even more compared to wild type Akt. [38][39][40] However, Akt-NLS markedly differed from wild type Akt in the transcriptional ability of the reprogramming factors. While Akt-WT upregulated the mRNA levels of Oct4, Sox2, cMyc and Nanog drastically Akt-NLS showed no increased expression except for cMyc mRNA.…”

Section: Discussionmentioning

confidence: 99%

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1

et al. 2015

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Cancer stem-like cells (CSCs) are a rare subpopulation of cancer cells capable of propagating the disease and causing cancer recurrence. In this study, we found that the cellular localization of PKB/Akt kinase affects the maintenance of CSCs. When Akt tagged with nuclear localization signal (Akt-NLS) was overexpressed in SKBR3 and MDA-MB468 cells, these cells showed a 10-15% increase in the number of cells with CSCs enhanced ALDH activity and demonstrated a CD44 CHigh /CD24 ¡Low phenotype. This effect was completely reversed in the presence of Aktspecific inhibitor, triciribine. Furthermore, cells overexpressing Akt or Akt-NLS were less likely to be in G0/G1 phase of the cell cycle by inactivating p21 Waf1/Cip1 and exhibited increased clonogenicity and proliferation as assayed by colony-forming assay (mammosphere formation). Thus, our data emphasize the importance the intracellular localization of Akt has on stemness in human breast cancer cells. It also indicates a new robust way for improving the enrichment and culture of CSCs for experimental purposes. Hence, it allows for the development of simpler protocols to study stemness, clonogenic potency, and screening of new chemotherapeutic agents that preferentially target cancer stem cells. Summary: The presented data, (i) shows new, stemness-promoting role of nuclear Akt/PKB kinase, (ii) it underlines the effects of nuclear Akt on cell cycle regulation, and finally (iii) it suggests new ways to study cancer stem-like cells.

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Section: Discussionmentioning

confidence: 99%

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1

et al. 2015

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“…Recently, two studies suggested the involvement of the MYC oncogene, which is downstream of the PI3K/mTOR pathway [31]. First, an unbiased screen showed that MYC conferred resistance to BEZ235 in the human mammary epithelial cell (HMEC) line MCF-10A, and that BEZ235-resistant human cell lines had higher c-MYC gene copy number compared to their sensitive counterparts [32].…”

Section: 4 + Bez235 In Vivomentioning

confidence: 99%

Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors

et al. 2014

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Combinatorial targeted therapies are more effective in treating cancer by blocking by-pass mechanisms or inducing synthetic lethality. However, their clinical application is hampered by resistance and toxicity. To meet this important challenge, we developed and tested a novel concept of biomarker-guided sequential applications of various targeted therapies using ErbB2-overexpressing/PTEN-low, highly aggressive breast cancer as our model. Strikingly, sustained activation of ErbB2 and downstream pathways drives trastuzumab resistance in both PTEN-low/ trastuzumab-resistant breast cancers from patients and mammary tumors with intratumoral heterogeneity from genetically-engineered mice. Although lapatinib initially inhibited trastuzumab-resistant mouse tumors, tumors bypassed the inhibition by activating the PI3K/mTOR signaling network as shown by the quantitative protein arrays. Interestingly, activation of the mTOR pathway was also observed in neoadjuvant lapatinib-treated patients manifesting lapatinib resistance. Trastuzumab + lapatinib resistance was effectively overcome by sequential application of a PI3K/mTOR dual kinase inhibitor (BEZ235) with no significant toxicity. However, our p-RTK array analysis demonstrated that BEZ235 treatment led to increased ErbB2 expression and phosphorylation in genetically-engineered mouse tumors and in 3-D, but not 2-D, culture, leading to BEZ235 resistance. Mechanistically, we identified ErbB2 protein stabilization and activation as a novel mechanism of BEZ235 resistance, which was reversed by subsequent treatment with lapatinib + BEZ235 combination. Remarkably, this sequential application of targeted therapies guided by biomarker changes in the tumors rapidly evolving resistance doubled the life-span of mice bearing exceedingly aggressive tumors. This fundamentally novel approach of using targeted therapies in a sequential order can effectively target and reprogram the signaling networks in cancers evolving resistance during treatment.

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“…forms heterodimers with MAX that sequentially access transcriptional sites in a cell proliferation direction (Zhu et al 2008, Ni et al 2013; (3) AR induces dissociation of repressor transcription factor 7-like 2 (TCF7L2) from the pioneer transcription factor of AR, FOXA1, promoting AR target gene MYC transcription with mitogenic action (Ni et al 2013). There is a positive feed-forward loop involving MYC in the regulation of androgendependent transcription in ER-negative HER2-positive BC subtype; (4) AR induces ErbB2 expression, which activates ERK.…”

Section: :10mentioning

confidence: 99%

Androgen receptor signaling pathways as a target for breast cancer treatment

Pietri¹,

Conteduca²,

Andreis³

et al. 2016

Endocrine-Related Cancer

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The androgen receptor (AR) is a ligand-dependent transcription factor, and its effects on breast range from physiological pubertal development and age-related modifications to cancer onset and proliferation. The prevalence of AR in early breast cancer is around 60%, and AR is more frequently expressed in ER-positive than in ER-negative tumors. We offer an overview of AR signaling pathways in different breast cancer subtypes, providing evidence that its oncogenic role is likely to be different in distinct biological and clinical scenarios. In particular, in ER-positive breast cancer, AR signaling often antagonizes the growth stimulatory effect of ER signaling; in triple-negative breast cancer (TNBC), AR seems to drive tumor progression (at least in luminal AR subtype of TNBC with a gene expression profile mimicking luminal subtypes despite being negative to ER and enriched in AR expression); in HER2-positive breast cancer, in the absence of ER expression, AR signaling has a proliferative role. These data represent the rationale for AR-targeting treatment as a potentially new target therapy in breast cancer subset using androgen agonists in some AR-positive/ER-positive tumors, AR antagonists in triple-negative/ AR-positive tumors and in combination with anti-HER2 agents or with other signaling pathways inhibitors (including PI3K/MYC/ERK) in HER2-positive/AR-positive tumors. Only the ongoing and future prospective clinical trials will allow us to establish which agents are the best option in every specific condition, keeping in mind that there is evidence of opposite androgens and AR agonist/antagonist drug effects on cell proliferation particularly in AR-positive/ER-positive tumors.

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Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1

Cited by 211 publications

References 24 publications

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1

Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors

Androgen receptor signaling pathways as a target for breast cancer treatment

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Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1

Cited by 211 publications

References 24 publications

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21Waf1/Cip1and p27kip1

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21Waf1/Cip1and p27kip1

Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors

Androgen receptor signaling pathways as a target for breast cancer treatment

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Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1

Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21^Waf1/Cip1and p27^kip1