Contributions of Yap and Taz dysfunction to breast cancer initiation, progression, and aging‐related susceptibility

Fresques, Tara; LaBarge, Mark A.

doi:10.1002/aac2.12011

Cited by 7 publications

(7 citation statements)

References 78 publications

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“…YAP and TAZ, the two Hippo-pathway downstream effectors of LATS1 signaling, have been associated with basal-like cell identity 70,[105][106][107][108] . To examine whether hyperactivation of YAP and/or TAZ upon depletion of LATS1 might drive the acquisition and maintenance of basal-like cell attributes in our experimental system, we established inducible knockdown of Yap or Taz in WT or Lats1-CKO basal-like-enriched cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Breast cancer plasticity is restricted by a LATS1-NCOR1 repressive axis

et al. 2022

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Breast cancer, the most frequent cancer in women, is generally classified into several distinct histological and molecular subtypes. However, single-cell technologies have revealed remarkable cellular and functional heterogeneity across subtypes and even within individual breast tumors. Much of this heterogeneity is attributable to dynamic alterations in the epigenetic landscape of the cancer cells, which promote phenotypic plasticity. Such plasticity, including transition from luminal to basal-like cell identity, can promote disease aggressiveness. We now report that the tumor suppressor LATS1, whose expression is often downregulated in human breast cancer, helps maintain luminal breast cancer cell identity by reducing the chromatin accessibility of genes that are characteristic of a “basal-like” state, preventing their spurious activation. This is achieved via interaction of LATS1 with the NCOR1 nuclear corepressor and recruitment of HDAC1, driving histone H3K27 deacetylation near NCOR1-repressed “basal-like” genes. Consequently, decreased expression of LATS1 elevates the expression of such genes and facilitates slippage towards a more basal-like phenotypic identity. We propose that by enforcing rigorous silencing of repressed genes, the LATS1-NCOR1 axis maintains luminal cell identity and restricts breast cancer progression.

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Section: Resultsmentioning

confidence: 99%

Breast cancer plasticity is restricted by a LATS1-NCOR1 repressive axis

et al. 2022

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“…Further, the “ Hippo-YAP Signaling Pathway ” was identified as the top contributing pathway to increased invasiveness during the feature selection process. The Hippo/YAP/TAZ pathway regulates a wide range of cancer phenotypes including cell proliferation, survival, EMT, anchorage independent growth, cell migration, invasion, and stemness 57 – 59 . In addition, top-ranked included pathways related to SREBP (or SREBF) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Multidimensional quantitative phenotypic and molecular analysis reveals neomorphic behaviors of p53 missense mutants

Pal,

Gonzalez-Malerva,

Eaton

et al. 2023

npj Breast Cancer

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Mutations in the TP53 tumor suppressor gene occur in >80% of the triple-negative or basal-like breast cancer. To test whether neomorphic functions of specific TP53 missense mutations contribute to phenotypic heterogeneity, we characterized phenotypes of non-transformed MCF10A-derived cell lines expressing the ten most common missense mutant p53 proteins and observed a wide spectrum of phenotypic changes in cell survival, resistance to apoptosis and anoikis, cell migration, invasion and 3D mammosphere architecture. The p53 mutants R248W, R273C, R248Q, and Y220C are the most aggressive while G245S and Y234C are the least, which correlates with survival rates of basal-like breast cancer patients. Interestingly, a crucial amino acid difference at one position—R273C vs. R273H—has drastic changes on cellular phenotype. RNA-Seq and ChIP-Seq analyses show distinct DNA binding properties of different p53 mutants, yielding heterogeneous transcriptomics profiles, and MD simulation provided structural basis of differential DNA binding of different p53 mutants. Integrative statistical and machine-learning-based pathway analysis on gene expression profiles with phenotype vectors across the mutant cell lines identifies quantitative association of multiple pathways including the Hippo/YAP/TAZ pathway with phenotypic aggressiveness. Further, comparative analyses of large transcriptomics datasets on breast cancer cell lines and tumors suggest that dysregulation of the Hippo/YAP/TAZ pathway plays a key role in driving the cellular phenotypes towards basal-like in the presence of more aggressive p53 mutants. Overall, our study describes distinct gain-of-function impacts on protein functions, transcriptional profiles, and cellular behaviors of different p53 missense mutants, which contribute to clinical phenotypic heterogeneity of triple-negative breast tumors.

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“…TAZ protein expression has been reported to increase from barely detectable in low-grade invasive ductal breast carcinomas to strong nuclear staining in ~80% of high-grade invasive ductal breast carcinomas [ 58 ]. Studies have associated TAZ expression levels with the TNBC subtype and amplification of the WWTR gene can explain only a fraction of the overexpression cases indicating that other mechanisms must be at play (reviewed in [ 59 ]). TAZ may be involved in the increased aggressiveness of TNBC by promoting breast cancer stem cell self-renewal and tumor initiation capacity [ 58 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

“…Studies have associated TAZ expression levels with the TNBC subtype and amplification of the WWTR gene can explain only a fraction of the overexpression cases indicating that other mechanisms must be at play (reviewed in [ 59 ]). TAZ may be involved in the increased aggressiveness of TNBC by promoting breast cancer stem cell self-renewal and tumor initiation capacity [ 58 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Triggers TAZ Phosphorylation in Basal A Triple Negative Breast Cancer Cells

Liu

Stel

Noord

et al. 2022

IJMS

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Hypoxia and HIF signaling drive cancer progression and therapy resistance and have been demonstrated in breast cancer. To what extent breast cancer subtypes differ in their response to hypoxia has not been resolved. Here, we show that hypoxia similarly triggers HIF1 stabilization in luminal and basal A triple negative breast cancer cells and we use high throughput targeted RNA sequencing to analyze its effects on gene expression in these subtypes. We focus on regulation of YAP/TAZ/TEAD targets and find overlapping as well as distinct target genes being modulated in luminal and basal A cells under hypoxia. We reveal a HIF1 mediated, basal A specific response to hypoxia by which TAZ, but not YAP, is phosphorylated at Ser89. While total YAP/TAZ localization is not affected by hypoxia, hypoxia drives a shift of [p-TAZ(Ser89)/p-YAP(Ser127)] from the nucleus to the cytoplasm in basal A but not luminal breast cancer cells. Cell fractionation and YAP knock-out experiments confirm cytoplasmic sequestration of TAZ(Ser89) in hypoxic basal A cells. Pharmacological and genetic interference experiments identify c-Src and CDK3 as kinases involved in such phosphorylation of TAZ at Ser89 in hypoxic basal A cells. Hypoxia attenuates growth of basal A cells and the effect of verteporfin, a disruptor of YAP/TAZ-TEAD–mediated transcription, is diminished under those conditions, while expression of a TAZ-S89A mutant does not confer basal A cells with a growth advantage under hypoxic conditions, indicating that other hypoxia regulated pathways suppressing cell growth are dominant.

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Contributions of Yap and Taz dysfunction to breast cancer initiation, progression, and aging‐related susceptibility

Cited by 7 publications

References 78 publications

Breast cancer plasticity is restricted by a LATS1-NCOR1 repressive axis

Breast cancer plasticity is restricted by a LATS1-NCOR1 repressive axis

Multidimensional quantitative phenotypic and molecular analysis reveals neomorphic behaviors of p53 missense mutants

Hypoxia Triggers TAZ Phosphorylation in Basal A Triple Negative Breast Cancer Cells

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