17β-Estradiol Activates HSF1 via MAPK Signaling in ERα-Positive Breast Cancer Cells

Vydra, Natalia; Janus, Patryk; Toma-Jonik, Agnieszka; Stokowy, Tomasz; Mrowiec, Katarzyna; Korfanty, Joanna; Długajczyk, Anna; Wojtaś, Bartosz; Gielniewski, Bartłomiej; Widłak, Wiesława

doi:10.3390/cancers11101533

Cited by 29 publications

(38 citation statements)

References 47 publications

(51 reference statements)

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“…Specifically, MLK3 depletion mimicked the Nutlin response and reduced both pSer326-HSF1 (Figure 5B) and HSF1 target gene expression (Figures 5C-D). Notably, MLK3 directly signals to the MEK/ERK stress pathway 60-62 and MEK/ERK activates HSF1 by phosphorylation 35, 63, 64 . In contrast, depletion of CDK1 or CDK2 failed to reduce pSer-325 HSF1 (Figures S5A-B).…”

Section: Resultsmentioning

confidence: 99%

Suppression of HSF1 activity by wildtype p53 creates the driving force for p53 loss-of-heterozygosity, enabling mutant p53 stabilization and invasion

Sener

Stender

Klemke

et al. 2020

Preprint

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HIGHLIGHTS 14 15• heterozygous p53 R248Q/+ tumors retain p53 transcriptional activity in a mouse model of 16 colorectal cancer (CRC) 17• wildtype p53 actively represses the tumor-promoting HSF1-regulated chaperone system 18 and proteotoxic stress response 19• the repressive WTp53 -HSF1 axis creates a selective pressure for WTp53 loss-of-20 heterozygosity in CRC tumors 21• p53 loss-of-heterozygosity enables stabilization of the gain-of-function p53 R248Q mutant 22 protein which in turn enables CRC invasion 23 24 25 26 27 28 29 30 2 31 Abstract 32A prerequisite for gain-of-function (GOF) p53 missense mutants (mutp53) is protein 33 stabilization. Moreover, a prerequisite for mutp53 stabilization is loss of the remaining wildtype 34 (WT) p53 allele (loss-of-heterozygosity, p53LOH) in mutp53/+ tumors. Thus, GOF, mutp53 35 stabilization and p53LOH are strictly linked. However, the driving force for p53LOH is unknown. 36Typically, heterozygous tumors are an instable transition state. Here we identify the repressive 37WTp53-HSF1 axis as the driver of p53LOH. 38We find that the WTp53 allele in AOM/DSS-induced colorectal tumors (CRC) of p53 R248Q/+ mice 39 retains its haploid transcriptional activity. Notably, WTp53 represses heat-shock factor 1 (HSF1) 40 activity, the master transcription factor of the proteotoxic stress defense response (HSR) that is 41 ubiquitously and constitutively activated in cancer tissues. HSR is critical for stabilizing 42 oncogenic proteins including mutp53. WTp53-retaining murine CRC tumors and tumor-derived 43 organoids and human CRC cells all suppress the tumor-promoting HSF1 transcriptional 44 program. 45Mechanistically, the retained WTp53 allele activates CDKN1A/p21, leading to cell cycle 46 inhibition and suppression of the E2F target gene MLK3. MLK3 links cell cycle to the MAPK 47 stress pathway to activate the HSR response. We show that in p53 R248Q/+ tumors WTp53 48 activation by constitutive stress (emanating from proliferative/metabolic stresses and genomic 49 instability) represses MLK3, consequently inactivating the MAPK-HSF1 response necessary to 50 ensure tumor survival. This creates strong selection pressure for p53LOH which eliminates the 51 repressive WTp53-HSF1 axis and unleashes the tumor-promoting HSF1 functions, inducing 52 mutp53 stabilization and enabling invasion. 53 54 Keywords 55 mutp53, HSF1, Hsp90, Hsp70, CDK4, MLK3, MAPK, AOM/DSS, colorectal cancer, organoids, 56 Idasanutlin 57 58 59 60 RESULTS 101 p53LOH is a prerequisite for mutp53 stabilization and invasion in colorectal cancer 102Stabilization of missense mutant p53 (mutp53) proteins specifically in tumor but not normal cells 103 is a key feature and prerequisite of GOF 16, 42 . Since p53LOH is a critical prerequisite for mutp53 104 stabilization in sarcomas and breast cancer 41 , we examined mutp53 stabilization before and 105 after p53LOH in the colorectal AOM/DSS model 9 . Briefly, we combined the humanized GOF 106

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Section: Resultsmentioning

confidence: 99%

Suppression of HSF1 activity by wildtype p53 creates the driving force for p53 loss-of-heterozygosity, enabling mutant p53 stabilization and invasion

Sener

Stender

Klemke

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Heat shock transcription factor 1 (HSF1), a member of the HSF family of transcription factors, regulates abnormal signals of tumour cells and promotes metastasis and metabolism of BC tumour cells. This finding suggests that HSF1 plays an important role in the occurrence and development of breast tumours [ 28 ]. PUF60, an oncogene, is highly expressed in BC tissue samples, and its high expression is closely related to the high lymph node metastasis rate and TNM stage of breast cancer [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Five-mRNA Signature for the Prognosis of Breast Cancer Based on the ceRNA Network

Shi¹,

Lin³

et al. 2020

BioMed Research International

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Background. The purpose of this study was to investigate the regulatory mechanisms of ceRNAs in breast cancer (BC) and construct a new five-mRNA prognostic signature. Methods. The ceRNA network was constructed by different RNAs screened by the edgeR package. The BC prognostic signature was built based on the Cox regression analysis. The log-rank method was used to analyse the survival rate of BC patients with different risk scores. The expression of the 5 genes was verified by the GSE81540 dataset and CPTAC database. Results. A total of 41 BC-adjacent tissues and 473 BC tissues were included in this study. A total of 2,966 differentially expressed lncRNAs, 5,370 differentially expressed mRNAs, and 359 differentially expressed miRNAs were screened. The ceRNA network was constructed using 13 lncRNAs, 267 mRNAs, and 35 miRNAs. Kaplan-Meier (K-M) methods showed that two lncRNAs (AC037487.1 and MIR22HG) are related to prognosis. Five mRNAs (VPS28, COL17A1, HSF1, PUF60, and SMOC1) in the ceRNA network were used to establish a prognostic signature. Survival analysis showed that the prognosis of patients in the low-risk group was significantly better than that in the high-risk group (p=0.0022). ROC analysis showed that this signature has a good diagnostic ability (AUC=0.77). Compared with clinical features, this signature was also an independent prognostic factor (HR: 1.206, 95% CI 1.108−1.311; p<0.001). External verification results showed that the expression of the 5 mRNAs differed between the normal and tumour groups at the chip and protein levels (p<0.001). Conclusions. These ceRNAs may play a key role in the development of BC, and the new 5-mRNA prognostic signature can improve the prediction of survival for BC patients.

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“…Interestingly, studies have suggested that HspB8 might play an important role in estrogen response and breast cancer progression. HspB8 is regulated by estrogen and can augment cancer cell progression by estrogenic stimuli [62][63][64], suggesting HspB8 might be a target associated with ER-positive tumors. However, the molecular mechanism should be further explored.…”

Section: Tumorigenesismentioning

confidence: 99%

Small Heat Shock Proteins in Cancers: Functions and Therapeutic Potential for Cancer Therapy

Xiong

Tan

et al. 2020

IJMS

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Small heat shock proteins (sHSPs) are ubiquitous ATP-independent chaperones that play essential roles in response to cellular stresses and protein homeostasis. Investigations of sHSPs reveal that sHSPs are ubiquitously expressed in numerous types of tumors, and their expression is closely associated with cancer progression. sHSPs have been suggested to control a diverse range of cancer functions, including tumorigenesis, cell growth, apoptosis, metastasis, and chemoresistance, as well as regulation of cancer stem cell properties. Recent advances in the field indicate that some sHSPs have been validated as a powerful target in cancer therapy. In this review, we present and highlight current understanding, recent progress, and future challenges of sHSPs in cancer development and therapy.

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17β-Estradiol Activates HSF1 via MAPK Signaling in ERα-Positive Breast Cancer Cells

Cited by 29 publications

References 47 publications

Suppression of HSF1 activity by wildtype p53 creates the driving force for p53 loss-of-heterozygosity, enabling mutant p53 stabilization and invasion

Suppression of HSF1 activity by wildtype p53 creates the driving force for p53 loss-of-heterozygosity, enabling mutant p53 stabilization and invasion

Five-mRNA Signature for the Prognosis of Breast Cancer Based on the ceRNA Network

Small Heat Shock Proteins in Cancers: Functions and Therapeutic Potential for Cancer Therapy

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