Language:

Three-dimensional modelling identifies novel genetic dependencies associated with breast cancer progression in the isogenic MCF10 model

The Journal of pathology, 2016-11, Vol.240 (3), p.315-328 [Peer Reviewed Journal]

2016 The Authors. published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. ;2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. ;Copyright © 2016 Pathological Society of Great Britain and Ireland ;ISSN: 0022-3417 ;EISSN: 1096-9896 ;DOI: 10.1002/path.4778 ;PMID: 27512948

Full text available

Citations Cited by

Actions
1. Add to My Research
2. Remove from My Research
3. E-mail
4. Print
5. Permalink
6. Citation
7. EasyBib
8. EndNote
9. RefWorks
10. Delicious
11. Export RIS
12. Export BibTeX

Title:
Three-dimensional modelling identifies novel genetic dependencies associated with breast cancer progression in the isogenic MCF10 model
Author: Maguire, Sarah L ; Peck, Barrie ; Wai, Patty T ; Campbell, James ; Barker, Holly ; Gulati, Aditi ; Daley, Frances ; Vyse, Simon ; Huang, Paul ; Lord, Christopher J ; Farnie, Gillian ; Brennan, Keith ; Natrajan, Rachael
Subjects: 3D spheroid assays ; breast cancer progression ; Breast Neoplasms - genetics ; Breast Neoplasms - pathology ; Carcinoma, Ductal, Breast - genetics ; Carcinoma, Ductal, Breast - pathology ; Carcinoma, Intraductal, Noninfiltrating - genetics ; Carcinoma, Intraductal, Noninfiltrating - pathology ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; Class I Phosphatidylinositol 3-Kinases ; Disease Progression ; DNA, Neoplasm - chemistry ; DNA, Neoplasm - genetics ; Exome - genetics ; Female ; Gene Expression Regulation, Neoplastic ; Genome ; High-Throughput Nucleotide Sequencing ; Humans ; Models, Biological ; Mutation ; next-generation sequencing ; Original Paper ; Original Papers ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - metabolism ; Pneumoviridae ; Sequence Analysis, DNA ; Spheroids, Cellular ; Transcriptome ; Tumor Suppressor Protein p53 - genetics
Is Part Of: The Journal of pathology, 2016-11, Vol.240 (3), p.315-328
Description: The initiation and progression of breast cancer from the transformation of the normal epithelium to ductal carcinoma in situ (DCIS) and invasive disease is a complex process involving the acquisition of genetic alterations and changes in gene expression, alongside microenvironmental and recognized histological alterations. Here, we sought to comprehensively characterise the genomic and transcriptomic features of the MCF10 isogenic model of breast cancer progression, and to functionally validate potential driver alterations in three‐dimensional (3D) spheroids that may provide insights into breast cancer progression, and identify targetable alterations in conditions more similar to those encountered in vivo. We performed whole genome, exome and RNA sequencing of the MCF10 progression series to catalogue the copy number and mutational and transcriptomic landscapes associated with progression. We identified a number of predicted driver mutations (including PIK3CA and TP53) that were acquired during transformation of non‐malignant MCF10A cells to their malignant counterparts that are also present in analysed primary breast cancers from The Cancer Genome Atlas (TCGA). Acquisition of genomic alterations identified MYC amplification and previously undescribed RAB3GAP1–HRAS and UBA2–PDCD2L expressed in‐frame fusion genes in malignant cells. Comparison of pathway aberrations associated with progression showed that, when cells are grown as 3D spheroids, they show perturbations of cancer‐relevant pathways. Functional interrogation of the dependency on predicted driver events identified alterations in HRAS, PIK3CA and TP53 that selectively decreased cell growth and were associated with progression from preinvasive to invasive disease only when cells were grown as spheroids. Our results have identified changes in the genomic repertoire in cell lines representative of the stages of breast cancer progression, and demonstrate that genetic dependencies can be uncovered when cells are grown in conditions more like those in vivo. The MCF10 progression series therefore represents a good model with which to dissect potential biomarkers and to evaluate therapeutic targets involved in the progression of breast cancer. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Publisher: Chichester, UK: John Wiley & Sons, Ltd
Language: English
Identifier: ISSN: 0022-3417
EISSN: 1096-9896
DOI: 10.1002/path.4778
PMID: 27512948
Source: MEDLINE
Alma/SFX Local Collection

Back to results list


INSPIRE LIBRARY - TON DUC THANG UNIVERSITY	(84-028) 37 755 057	Feedback
19 Nguyen Huu Tho St. Dist.7, HCM	thuvien@tdtu.edu.vn	Feedback

Three-dimensional modelling identifies novel genetic dependencies associated with breast cancer progression in the isogenic MCF10 model

Searching Remote Databases, Please Wait