Halting triple negative breast cancer by targeting PROCR

Fu, Nai Yang; Visvader, Jane E.

doi:10.1038/s41422-019-0245-5

Cited by 5 publications

(5 citation statements)

References 10 publications

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“…Breast cancer is the most common malignancy among women worldwide, and about one in eight to ten women is likely to get breast cancer in their lifetime [ 1 , 2 ]. Benefiting from early detection and efficient systemic therapies [ 3 – 5 ], deaths from breast cancer are decreasing in North America and west European countries [ 6 ]. However, breast cancer is still one of the most common causes of cancer-related death in developing countries [ 1 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

The noncoding RNAs SNORD50A and SNORD50B-mediated TRIM21-GMPS interaction promotes the growth of p53 wild-type breast cancers by degrading p53

Feng

Wang

et al. 2021

Cell Death Differ

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Small nucleolar RNA SNORD50A and SNORD50B (SNORD50A/B) has been reported to be recurrently deleted and function as a putative tumor suppressor in different types of cancer by binding to and suppressing the activity of the KRAS oncoproteins. Its deletion correlates with poorer patient survival. However, in this study, we surprisingly found that SNORD50A/B loss predicted a better survival in breast cancer patients carrying wild-type p53. Functional studies showed that SNORD50A/B deletion strongly inhibited the proliferation, migration, invasion and tumorigenic potential, and induced cell cycle arrest and apoptosis in p53 wild-type breast cancer cells, while exerted the opposite effects in p53 mutated breast cancer cells. This was also supported by ectopically expressing SNORD50A/B in both p53 wild-type and mutated breast cancer cells. Mechanistically, SNORD50A/B clearly enhances the interaction between E3 ubiquitin ligase TRIM21 and its substrate GMPS by forming a complex among them, thereby promoting GMPS ubiquitination and its subsequent cytoplasmic sequestration. SNORD50A/B deletion in p53 wild-type breast cancer cells will release GMPS and induce the translocation of GMPS into the nucleus, where GMPS can recruit USP7 and form a complex with p53, thereby decreasing p53 ubiquitination, stabilizing p53 proteins, and inhibiting malignant phenotypes of cancer cells. Altogether, the present study first reports that SNORD50A/B plays an oncogenic role in p53 wild-type breast cancers by mediating TRIM21-GMPS interaction.

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Section: Introductionmentioning

confidence: 99%

The noncoding RNAs SNORD50A and SNORD50B-mediated TRIM21-GMPS interaction promotes the growth of p53 wild-type breast cancers by degrading p53

Feng

Wang

et al. 2021

Cell Death Differ

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“…In the breast cancer context, EPCR + TNBC cells exhibit stem cell-like properties and show enhanced tumor-initiating activity [ 40 ]. EPCR is highly expressed in aggressive basal-like breast cancer and used as a specific marker for CSCs in TNBC [ 20 , 21 ]. Interestingly, all individual ATP8B3, FOXR2, FRG2 and HIST1H4A KOs significantly increased EPCR positive (EPCR+) cell numbers (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We further showed that CRISPR-induced specific loss-of-function deletion of these genes led to paclitaxel resistance in TNBC cells. Interestingly, we found several of these genes (ATP8B3, FOXR2, FRG2, HIST1H4A) to act as cancer stemness regulators, able to regulate cancer stem cell self-renewal activity and expression of the endothelial protein C receptor (EPCR), a specific stemness marker for TNBC [ 20 , 21 ]. We also showed that FRG2 gene deletion reduced paclitaxel efficacy and promoted tumor metastasis in an in vivo orthotopic transplantation TNBC model.…”

Section: Introductionmentioning

confidence: 99%

Combined in vitro/in vivo genome-wide CRISPR screens in triple negative breast cancer identify cancer stemness regulators in paclitaxel resistance

Yan,

Dai,

Poulet

et al. 2023

Oncogenesis

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Triple negative breast cancer (TNBC) is defined as lacking the expressions of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC patients exhibit relatively poor clinical outcomes due to lack of molecular markers for targeted therapies. As such chemotherapy often remains the only systemic treatment option for these patients. While chemotherapy can initially help shrink TNBC tumor size, patients eventually develop resistance to drug, leading to tumor recurrence. We report a combined in vitro/in vivo genome-wide CRISPR synthetic lethality screening approach in a relevant TNBC cell line model to identify several targets responsible for the chemotherapy drug, paclitaxel resistance. Computational analysis integrating in vitro and in vivo data identified a set of genes, for which specific loss-of-function deletion enhanced paclitaxel resistance in TNBC. We found that several of these genes (ATP8B3, FOXR2, FRG2, HIST1H4A) act as cancer stemness negative regulators. Finally, using in vivo orthotopic transplantation TNBC models we showed that FRG2 gene deletion reduced paclitaxel efficacy and promoted tumor metastasis, while increasing FRG2 expression by means of CRISPR activation efficiently sensitized TNBC tumors to paclitaxel treatment and inhibited their metastatic abilities. In summary, the combined in vitro/in vivo genome-wide CRISPR screening approach proved effective as a tool to identify novel regulators of paclitaxel resistance/sensitivity and highlight the FRG2 gene as a potential therapeutical target overcoming paclitaxel resistance in TNBC.

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“…Up to date, an effective therapeutic for breast cancer has been lacking in the clinical 3,15 . Despite the different treatments, including surgery, radiotherapy, chemotherapy, and endocrine therapy have been routinely applied for breast cancer 3,16,17 . However, a part of patients will still get recurrence and metastasis.…”

Section: Discussionmentioning

confidence: 99%

The Low Expression of MEOX2 is Associated With Poorer Survival in Breast Cancer

Wang

Tang

Wang³

et al. 2021

Preprint

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The regulation of vertebrate limb myogenesis gene, Mesenchyme Homeobox 2 (MEOX2), has been reported to be associated with most cancer progression closely. However, its role and function in breast cancer are unidentified. Here, we aim to investigate the association of MEOX2 expression with clinicopathological features and the survival probability of breast cancer. The MEOX2 expression in breast cancer was first analyzed from The Cancer Genome Atlas (TCGA) database. Then, the association of MEOX2 with patients’ clinicopathological variables and prognostic probability were detected by bioinformatics analysis. Moreover, a high-throughput tissue microarray containing 135 cases of breast cancer was used to further clarify the expression of MEOX2 in breast cancer patients. The expression of MEOX2 is inhibited in breast cancer than in normal tissues, and the lower MEOX2 expression indicates the poorer prognosis of breast cancer patients. In addition, the histological grade of MEOX2 expression is negatively correlated with the Ki67 level. Multivariate COX regression also verified that MEOX2 was an independent prognostic factor in breast cancer patients. Based on our results, we can conclude that lower MEOX2 expression was related to tumor proliferation and could be a new diagnostic and prognostic biomarker of breast cancer.

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Halting triple negative breast cancer by targeting PROCR

Cited by 5 publications

References 10 publications

The noncoding RNAs SNORD50A and SNORD50B-mediated TRIM21-GMPS interaction promotes the growth of p53 wild-type breast cancers by degrading p53

The noncoding RNAs SNORD50A and SNORD50B-mediated TRIM21-GMPS interaction promotes the growth of p53 wild-type breast cancers by degrading p53

Combined in vitro/in vivo genome-wide CRISPR screens in triple negative breast cancer identify cancer stemness regulators in paclitaxel resistance

The Low Expression of MEOX2 is Associated With Poorer Survival in Breast Cancer

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