Re-definition of <i>claudin-low</i> as a breast cancer phenotype

Fougner, Christian; Bergholtz, Helga; Norum, Jens Henrik; Sørlie, Thérese

doi:10.1101/756411

Cited by 9 publications

(18 citation statements)

References 37 publications

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“…To determine whether high expression of the GLIS2 signature is a hallmark of claudin-low tumors across breast cancers in general, we compared the expression of GLIS2 target genes in 1082 breast cancers, using a public dataset from The Cancer Genome Atlas (TCGA) (38). We found that high expression of GLIS2 target genes enables the segregation of claudin-low tumors from other breast tumors in a manner similar to the Prat et al (37) reference panel of genes used to mark claudin-low cancers (Fig.…”

Section: Primary Cilium-dependent Regulation Of Glis2 Controls Claudin-low Matic Stemness and Tumorigenicitymentioning

confidence: 99%

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An EMT–primary cilium–GLIS2 signaling axis regulates mammogenesis and claudin-low breast tumorigenesis

et al. 2021

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The epithelial-mesenchymal transition (EMT) and primary ciliogenesis induce stem cell properties in basal mammary stem cells (MaSCs) to promote mammogenesis, but the underlying mechanisms remain incompletely understood. Here, we show that EMT transcription factors promote ciliogenesis upon entry into intermediate EMT states by activating ciliogenesis inducers, including FGFR1. The resulting primary cilia promote ubiquitination and inactivation of a transcriptional repressor, GLIS2, which localizes to the ciliary base. We show that GLIS2 inactivation promotes MaSC stemness, and GLIS2 is required for normal mammary gland development. Moreover, GLIS2 inactivation is required to induce the proliferative and tumorigenic capacities of the mammary tumorinitiating cells (MaTICs) of claudin-low breast cancers. Claudin-low breast tumors can be segregated from other breast tumor subtypes based on a GLIS2-dependent gene expression signature. Collectively, our findings establish molecular mechanisms by which EMT programs induce ciliogenesis to control MaSC and MaTIC stemness, mammary gland development, and claudin-low breast cancer formation.

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Section: Primary Cilium-dependent Regulation Of Glis2 Controls Claudin-low Matic Stemness and Tumorigenicitymentioning

confidence: 99%

“…For gene expression analysis across breast tumor subtypes, the pipeline from Fougner et al (38) was used on the TCGA-BRCA Dataset (github.com/clfougner/ClaudinLow). For ChIP-seq analysis, previously reported genome-wide murine Snail binding sites elucidated using ChIP-seq were obtained from the GEO (GSE61198).…”

Section: Gene Expression and Chip-seq Analysesmentioning

confidence: 99%

An EMT–primary cilium–GLIS2 signaling axis regulates mammogenesis and claudin-low breast tumorigenesis

et al. 2021

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“…This phenotype involves various intrinsic subtypes associated with high immune and stromal infiltration levels and a low mutation burden, proliferation, and genomic instability. 14…”

Section: Introductionmentioning

confidence: 99%

Emerging Therapeutic Drugs in Metastatic Triple-Negative Breast Cancer

Cipriano

Mesquita

2021

Breast Cancer�(Auckl)

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Metastatic triple-negative breast cancer (TNBC) is a heterogeneous disease with a poor prognosis and currently with few treatment options. Treatment of these patients is highly based on systemic chemotherapy. Some targeted drugs were recently approved for these patients: two poly(ADP-ribose) polymerase inhibitors in patients with germline BRCA1/2 mutations (olaparib and talazoparib), immune checkpoint inhibitors in association with chemotherapy if programmed death-ligand 1 positive (atezolizumab plus nabpaclitaxel and pembrolizumab plus chemotherapy [nabpaclitaxel, paclitaxel, and carboplatin plus gemcitabine]), and an antibody-drug conjugate sacituzumab-govitecan in heavily pretreated patients (at least 2 previous lines for the metastatic setting). Combinations using these and other targeted treatment options are under investigation in early and late clinical trials, and we will probably have some practice-changing results in the new future. Other targeted drugs explored in phase II and phase III clinical trials are PI3K/AKT pathway inhibitors and androgen receptor antagonists in patients with alterations in these signaling pathways. The definition of molecular subtypes has been essential for the development of these treatment strategies. Soon, the treatment of metastatic TNBC could be based on personalized medicine using molecular testing for targeted drugs instead of only systemic chemotherapy. The authors present a review of emerging treatment options in metastatic TNBC, focusing on targeted drugs, including the recent data published in 2020.

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“…Third, the spatially heterogenous distribution of WTP+ and WTP-niches at primary tumor periphery parallels the enrichment of post-EMT cells at tumor invasion fronts (39) and heterogeneous EMT transition states localized in different niches (40). Fourth, human residual breast cancers resistant to neoadjuvant ET (letrozole) or CT (docetaxel) display mesenchymal and tumor-initiating features correlative with poor prognosis (41), even though the corresponding gene expression marker was linked to a specific type of molecular subtype (-claudin-low‖) rather than a pan-cancer marker independent of breast cancer molecular subtyping (42). Despite these lines of indirect evidence, the ultimate confirmation of the EMT nature of WTP will require changes in a set of molecular markers and cellular properties (43) to synchronize with the WTP marker of 2.8-mm niche-scale extracellular matrix remodeling (44).…”

Section: Discussionmentioning

confidence: 99%

Wound-like tumor periphery in human breast cancer predicts a convergent drug nonresponse

Liao

et al. 2021

Preprint

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A significant portion of breast cancer patients are nonresponsive to well-established drugs and destined for a poor outcome regardless of molecular subtype. Although several (multiparameter) molecular markers have predicted their resistance to some of these drugs, profound uniparameter markers predictive of a convergent nonresponse to all these drugs remain elusive. We employ co-registered standard-multiphoton histology to representatively sample a few peripheral niches of the primary tumor, so that hundreds of patients can be stratified with either a wound-like or non-wound tumor periphery. With no fitting variable, this simple uniparameter morphological marker is: (a) highly sensitive and specific to predict a multidrug-nonresponsive phenotype that accounts for the majority of recurrence or death, independent of the molecular subtype or related adjuvant drug selection, clinical endpoint (disease-free versus overall survival), and hosting medical center; (b) robust against intratumor heterogeneity and valid at the earliest clinicopathological stage; and (c) dominant in predicting prognosis in the context of routine clinicopathological markers. Considering the mechanistic link between a wound-like extracellular matrix and a microenvironment supporting migratory or mesenchymal tumor cells, we attribute these unusual capabilities to an epithelial-mesenchymal transition nature of the morphological marker long sought after by pathologists.

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Re-definition of claudin-low as a breast cancer phenotype

Cited by 9 publications

References 37 publications

An EMT–primary cilium–GLIS2 signaling axis regulates mammogenesis and claudin-low breast tumorigenesis

An EMT–primary cilium–GLIS2 signaling axis regulates mammogenesis and claudin-low breast tumorigenesis

Emerging Therapeutic Drugs in Metastatic Triple-Negative Breast Cancer

Wound-like tumor periphery in human breast cancer predicts a convergent drug nonresponse

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