Intracellular amphiregulin is critical for heterochromatin maintenance and genomic stability in response to replication stress inBRCA2mut/+mammary epithelial cells DOI

Tianqi Jiang,

Aiman A. Zein,

M.A. Christine Pratt

et al.

Published: Oct. 29, 2024

Abstract The BRCA2 tumor suppressor protein has roles in homologous recombination DNA repair and replication fork protection carriers of mutation the gene ( mut/+ ) are at high risk for breast cancers as a consequence genomic instability. Mammary epithelial cells (MECs) subjected to significant hormone-driven replication. MECs must therefore be able mitigate RS-induced chronic damage that could result cell death or senescence. In response acute RS hTERT-MECs, we have found EGFR ligand, amphiregulin (AREG) rapidly undergoes retrograde trafficking nucleus nuclear membrane (NM) association with lamin A resulting transient increase H3K9me3 heterochromatin most markedly hTERT-MECs. promoted NM incorporation prelamin was dependent on endogenous but not exogenous AREG. Prelamin is reported stabilize SUV39h1 expression C-terminal truncated AREG translocates increased SUV39h1, HP1α H3K9me3. knockdown reduced both accompanied by massive decompaction reduction global heterochromatin. Loss upon depletion damage, speed resulted firing new multiple origins. Knockdown also impacted activation type-1 interferon (IFN)-like promoting Chronic stimulated along FOXM1 ESR1 mRNA protein. Consistent this, AREG, ERα were detected hyperplastic regions human tissue. Overall, our work reveals critical unanticipated role maintenance induction preventing excessive senescence MECs. Since promotes expression, this may link aberrant expansion estrogen receptor-expressing mammary

Language: Английский

Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets DOI Creative Commons
Shaosen Zhang,

Xinyi Xiao,

Yonglin Yi

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: June 18, 2024

Abstract Tumorigenesis is a multistep process, with oncogenic mutations in normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic and expansion tissues, their transformation into cancer remains rare event, indicating presence of additional driver events for progression to an irreversible, highly heterogeneous, invasive lesion. Recently, researchers are emphasizing mechanisms environmental tumor risk factors epigenetic alterations that profoundly influencing early malignant evolution, independently inducing mutations. Additionally, evolution tumorigenesis reflects multifaceted interplay between cell-intrinsic identities various cell-extrinsic exert selective pressures either restrain uncontrolled proliferation or allow specific clones progress tumors. by which induce both intrinsic cellular competency remodel stress facilitate not fully understood. In this review, we summarize genetic, epigenetic, external events, effects on co-evolution transformed cells ecosystem during initiation evolution. A deeper understanding earliest molecular holds promise translational applications, predicting individuals at high-risk developing strategies intercept transformation.

Language: Английский

Citations

55
Single-cell analyses reveal evolution mimicry during the specification of breast cancer subtype DOI Creative Commons

Zhijie Gao,

Huan Fang,

Si Sun

et al.

Theranostics, Journal Year: 2024, Volume and Issue: 14(8), P. 3104 - 3126

Published: Jan. 1, 2024

Background:The stem or progenitor antecedents confer developmental plasticity and unique cell identities to cancer cells via genetic epigenetic programs.A comprehensive characterization mapping of the cell-of-origin breast using novel technologies unveil subtype-specific therapeutic targets is still absent.Methods: We integrated 195,144 high-quality from normal tissues 406,501 primary samples create a large-scale single-cell atlas human cancerous breasts.Potential heterogeneous origin malignant was explored by contrasting against reference epithelial cells.Multi-omics analyses both in vitro vivo experiments were performed screen validate potential treatment targets.Novel biomarkers identified immune stromal subpopulations validated immunohistochemistry our cohort.Results: Tumor stratification based on patterns correlated with clinical outcomes, genomic aberrations diverse microenvironment constitutions.We found that luminal (LP) subtype robustly associated poor prognosis, instability dysfunctional microenvironment.However, LP patients sensitive neoadjuvant chemotherapy (NAC), PARP inhibitors (PARPi) immunotherapy.The target PLK1 investigated experiments.Besides, profiling inspired us identify range clinically relevant subpopulations, including subsets innate lymphoid (ILCs), macrophages endothelial cells. Conclusion:The present study revealed cellular repertoire cancer.Combining bulk transcriptome data, we elucidated evolution mimicry subtypes expounded vital implications.Novel could be targets.Taken together, Our findings lay foundation for precise prognostic cancer.

Language: Английский

Citations

7
Emerging strategies to investigate the biology of early cancer DOI
Ran Zhou, Xiwen Tang, Yuan Wang

et al.

Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: 24(12), P. 850 - 866

Published: Oct. 21, 2024

Language: Английский

Citations

5
Cells-of-Origin of Breast Cancer and Intertumoral Heterogeneity DOI
Rachel Joyce, Jane E. Visvader

Advances in experimental medicine and biology, Journal Year: 2025, Volume and Issue: unknown, P. 151 - 165

Published: Jan. 1, 2025

Language: Английский

Citations

0
Fibroblast hierarchy dynamics during mammary gland morphogenesis and tumorigenesis DOI Creative Commons
Rosa Pascual, Jinming Cheng,

A. Smet

et al.

The EMBO Journal, Journal Year: 2025, Volume and Issue: unknown

Published: April 11, 2025

Abstract Fibroblasts form a major component of the stroma in normal mammary tissue and breast tumors. Here, we have applied longitudinal single-cell transcriptome profiling >45,000 fibroblasts mouse gland across five different developmental stages during oncogenesis. In gland, diverse stromal populations were resolved, including lobular-like fibroblasts, committed preadipocytes adipogenesis-regulatory, as well cycling puberty pregnancy. These specialized cell types appear to emerge from CD34 high mesenchymal progenitor cells, accompanied by elevated Hedgehog signaling. During late tumorigenesis, heterogeneous cancer-associated (CAFs) identified models cancer, population – myofibroblastic CAFs (myCAFs) that transcriptionally phenotypically similar senescent CAFs. Moreover, Wnt9a was demonstrated be regulator senescence myCAFs. findings reflect hierarchically organized compartment provides framework better understand cancerous states.

Language: Английский

Citations

0
Cell origin of BRCA2-mutant breast cancer DOI
Jiahui Xu, Suling Liu

Nature Cell Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Language: Английский

Citations

1
The prognostic genes model of breast cancer drug resistance based on single-cell sequencing analysis and transcriptome analysis DOI Creative Commons
Yao Liu, Lun Dong, Jing Ma

et al.

Clinical and Experimental Medicine, Journal Year: 2024, Volume and Issue: 24(1)

Published: May 25, 2024

Abstract Breast cancer (BC) represents a multifaceted malignancy, with escalating incidence and mortality rates annually. Chemotherapy stands as an indispensable approach for treating breast cancer, yet drug resistance poses formidable challenge. Through transcriptome data analysis, we have identified two sets of genes exhibiting differential expression in this context. Furthermore, confirmed the overlap between these those associated exosomes, which were subsequently validated cell lines. The investigation screened to determine prognostic markers BC utilized them formulate model. disparities prognosis immunity high- low-risk groups using test dataset. We discerned different subtypes based on levels samples. Variations prognosis, immunity, sensitivity among distinct examined. Leveraging from single-cell sequencing gene expression, AUCell algorithm was employed score individual clusters analyze pathways implicated high-scoring groups. Prognostic (CCT4, CXCL13, MTDH, PSMD2, RAB27A) subsewoquently RT-qPCR. Consequently, established model predicting that hinges ERGs. evaluated value can now serve reference precise treatment condition.

Language: Английский

Citations

1
A comprehensive luminal breast cancer patient‐derived xenografts (PDX) library to capture tumor heterogeneity and explore the mechanisms of resistance to CDK4/6 inhibitors DOI Creative Commons
Ilenia Segatto, Maria Chiara Mattevi, Gian Luca Rampioni Vinciguerra

et al.

The Journal of Pathology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 25, 2024

Abstract Breast cancer (BC) is marked by significant genetic, morphological and clinical heterogeneity. To capture this heterogeneity unravel the molecular mechanisms driving tumor progression drug resistance, we established a comprehensive patient‐derived xenograft (PDX) biobank, focusing particularly on luminal (estrogen receptor, ER+) young premenopausal patients, for whom PDX models are currently scarce. Across all BC subtypes, our efforts resulted in an overall success rate of 17% (26 lines out 151 total attempts), specifically 15% luminal, 12% human epidermal growth factor receptor 2 positive (HER2+) 35% triple negative BC. These mirrored morphologic genetic features from which they originated, serving as reliable tool to investigate resistance test therapeutic strategies. We focused understanding CDK4/6 inhibitors (CDK4/6i), crucial treatment patients with advanced Treating sensitive CDK4/6i palbociclib revealed that, despite initial shrinkage, some tumors might eventually regrow under treatment. RNA sequencing, followed gene set enrichment analyses, unveiled that these PDXs have become refractory CDK4/6i, both at biological levels, displaying proliferation pathways, such MTORC1 , E2F MYC . Using organoids derived (PDxO), observed acquisition conferred cross‐resistance endocrine therapy targeting was successful strategy overcome resistance. Considered together, results indicate may serve robust tools elucidate basis disease and, providing possibility simultaneously different therapies same tumor, surmount While approach course not feasible clinic, its exploitation expedite identification development more © 2024 The Author(s). Journal Pathology published John Wiley & Sons Ltd behalf Pathological Society Great Britain Ireland.

Language: Английский

Citations

1
Novel Cancer Prevention Strategies in Individuals With Hereditary Cancer Syndromes: Focus on BRCA1, BRCA2, and Lynch Syndrome DOI
Charles M. Bowen, Kaitlin Demarest, Eduardo Vilar

et al.

American Society of Clinical Oncology Educational Book, Journal Year: 2024, Volume and Issue: 44(3)

Published: June 1, 2024

Germline pathogenic variants (PVs) in the BRCA1 and BRCA2 genes confer elevated risks of breast, ovarian, other cancers. Lynch syndrome (LS) is associated with increased multiple cancer types including colorectal uterine Current risk mitigation strategies have focused on pharmacologic reduction, enhanced surveillance, preventive surgeries. While these approaches can be effective, they stand to improved because either limited efficacy or undesirable impact quality life. The current review summarizes ongoing investigational efforts prevention for patients germline PVs BRCA1, BRCA2, LS-associated genes. These span radiation, surgery, pharmacology vaccine strategies. Understanding molecular events involved premalignant malignant transformation high-risk individuals may ultimately contribute significantly novel

Language: Английский

Citations

0
Midkine links aging with breast cancer—A new predictor of cancer risk DOI
Jane E. Visvader

Cancer Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Language: Английский

Citations

0