Stress hormones reduce the efficacy of paclitaxel in triple negative breast cancer through induction of DNA damage

Reeder, Alex; Attar, Myriam A.; Nazario, L. Arlene; Bathula, Chandra S.; Zhang, A.; Hochbaum, Daniel; Roy, E. P.; Cooper, Kristine L.; Oesterreich, Steffi; Davidson, Nancy E.; Neumann, Carola A.; Flint, Melanie S.

doi:10.1038/bjc.2015.133

Cited by 73 publications

(73 citation statements)

References 45 publications

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“…ATM is a well-known PI3KK activated by DNA damage such as DNA doublestrand breaks, which phosphorylates several target proteins associated with the DNA damage response (Marechal and Zou 2013). GC is one of the stress hormones that induces DNA damage (Flint et al 2007;Lupien et al 2007;Flint and Bovbjerg 2012;Reeder et al 2015). The induced DNA damage could activate ATM kinase and phosphorylate UPF1 in the presence of GC, consequently enhancing GMD efficiency.…”

Section: Discussionmentioning

confidence: 99%

Identification and molecular characterization of cellular factors required for glucocorticoid receptor-mediated mRNA decay

Park

et al. 2016

Genes Dev.

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Glucocorticoid (GC) receptor (GR) has been shown recently to bind a subset of mRNAs and elicit rapid mRNA degradation. However, the molecular details of GR-mediated mRNA decay (GMD) remain unclear. Here, we demonstrate that GMD triggers rapid degradation of target mRNAs in a translation-independent and exon junction complexindependent manner, confirming that GMD is mechanistically distinct from nonsense-mediated mRNA decay (NMD). Efficient GMD requires PNRC2 (proline-rich nuclear receptor coregulatory protein 2) binding, helicase ability, and ATM-mediated phosphorylation of UPF1 (upstream frameshift 1). We also identify two GMD-specific factors: an RNA-binding protein, YBX1 (Y-box-binding protein 1), and an endoribonuclease, HRSP12 (heat-responsive protein 12). In particular, using HRSP12 variants, which are known to disrupt trimerization of HRSP12, we show that HRSP12 plays an essential role in the formation of a functionally active GMD complex. Moreover, we determine the hierarchical recruitment of GMD factors to target mRNAs. Finally, our genome-wide analysis shows that GMD targets a variety of transcripts, implicating roles in a wide range of cellular processes, including immune responses.

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Section: Discussionmentioning

confidence: 99%

Identification and molecular characterization of cellular factors required for glucocorticoid receptor-mediated mRNA decay

Park

et al. 2016

Genes Dev.

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“…β-adrenergic signaling can inhibit DNA damage repair 60–62 and p53-associated apoptosis 54 , raising the possibility that SNS activity might potentially contribute to tumour initiation or chromosomal instability. Several molecular pathways have been implicated in β-adrenergic inhibition of DNA damage repair, including activation of the ataxia-telangiectasia and Rad3-related (ATR)/p21 pathway 62 and β-arrestin-induced activation of the AKT signaling pathway, which stimulates the E3 ubiquitin ligase murine double minute 2 (MDM2) to degrade p53 protein and thereby inhibit p53-mediated responses to chromosomal damage 60 .…”

Section: Sns Regulation Of Cancer Biologymentioning

confidence: 99%

“…Several molecular pathways have been implicated in β-adrenergic inhibition of DNA damage repair, including activation of the ataxia-telangiectasia and Rad3-related (ATR)/p21 pathway 62 and β-arrestin-induced activation of the AKT signaling pathway, which stimulates the E3 ubiquitin ligase murine double minute 2 (MDM2) to degrade p53 protein and thereby inhibit p53-mediated responses to chromosomal damage 60 . These effects are sufficient to increase the prevalence of spontaneous chromosomal aberrations in tissues such as the thymus and brain, and such effects can be efficiently blocked by the β-adrenergic antagonist propranolol 60,61 .…”

Section: Sns Regulation Of Cancer Biologymentioning

confidence: 99%

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Sympathetic nervous system regulation of the tumour microenvironment

et al. 2015

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The peripheral autonomic nervous system (ANS) is known to regulate gene expression in primary tumours and their surrounding microenvironment. Activation of the sympathetic division of the ANS in particular modulates gene expression programs that promote metastasis of solid tumours by stimulating macrophage infiltration, inflammation, angiogenesis, epithelial-mesenchymal transition, and tumour invasion, and by inhibiting cellular immune responses and programmed cell death. Haematological cancers are modulated by sympathetic nervous system (SNS) regulation of stem cell biology and hematopoietic differentiation programs. In addition to identifying a molecular basis for physiologic stress effects on cancer, these findings have also identified new pharmacologic strategies to inhibit cancer progression in vivo.

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“…Tumor cells also express βARs (Pon et al, 2016; Reeder et al, 2015), and activation of βAR signaling increases invasion of tumor cells, as measured by in vitro assays (Creed et al, 2015; Kim-Fuchs et al, 2014; Pon et al, 2016; Yamazaki et al, 2014) and in explant cultures (Creed et al, 2015). Previously, we discovered that the β 2 AR-selective agonist formoterol, but not the β 1 AR-selective agonist xamoterol, induced the formation of invadopodia in breast cancer cells (Creed et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

β 2 -Adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer

Chang

Walker

et al. 2016

Brain, Behavior, and Immunity

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Chronic stress accelerates metastasis - the main cause of death in cancer patients - through the activation of β-adrenoceptors (βARs). We have previously shown that β2AR signaling in MDA-MB-231HM breast cancer cells, facilitates invadopodia formation and invasion in vitro. However, in the tumor microenvironment where many stromal cells also express βAR, the role of β2AR signaling in tumor cells in metastasis is unclear. Therefore, to investigate the contribution of β2AR signaling in tumor cells to metastasis in vivo, we used RNA interference to generate MDA-MB-231HM breast cancer cells that are deficient in β2AR. β2AR knockdown in tumor cells reduced the proportion of cells with a mesenchymal-like morphology and, as expected, reduced tumor cell invasion in vitro. Conversely, overexpression of β2AR in low metastatic MCF-7 breast cancer cells induced an invasive phenotype. Importantly, we found that knockdown of β2AR in tumor cells significantly reduced the impact of stress on metastasis in vivo. These findings highlight a crucial role for β2AR tumor cell signaling in the adverse effects of stress on metastasis, and indicate that it may be necessary to block β2AR on tumor cells to fully control metastatic progression.

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Stress hormones reduce the efficacy of paclitaxel in triple negative breast cancer through induction of DNA damage

Cited by 73 publications

References 45 publications

Identification and molecular characterization of cellular factors required for glucocorticoid receptor-mediated mRNA decay

Identification and molecular characterization of cellular factors required for glucocorticoid receptor-mediated mRNA decay

Sympathetic nervous system regulation of the tumour microenvironment

β 2 -Adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer

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