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Genomic insights into triple-negative and HER2-positive breast cancers using isogenic model systems.

ABSTRACT: INTRODUCTION: In general, genomic signatures of breast cancer subtypes have little or no overlap owing to the heterogeneous genetic backgrounds of study samples. Thus, obtaining a reliable signature in the context of isogenic nature of the cells has been challenging and the precise contribution of isogenic triple negative breast cancer (TNBC) versus non-TNBC remains poorly defined. METHODS: We established isogenic stable cell lines representing TNBC and Human Epidermal Growth Factor Receptor 2 positive (HER2+) breast cancers by introducing HER2 in TNBC cell lines MDA-MB-231 and MDA-MB-468. We examined protein level expression and functionality of the transfected receptor by treatment with an antagonist of HER2. Using microarray profiling, we obtained a comprehensive gene list of differentially expressed between TNBC and HER2+ clones. We identified and validated underlying isogenic components using qPCR and also compared results with expression data from patients with similar breast cancer subtypes. RESULTS: We identified 544 and 1087 statistically significant differentially expressed genes between isogenic TNBC and HER2+ samples in MDA-MB-231 and MDA-MB-468 backgrounds respectively and a shared signature of 49 genes. By comparing results from MDA-MB-231 and MDA-MB-468 backgrounds with two patient microarray datasets, we identified 17 and 22 common genes with same expression trend respectively. Additionally, we identified 56 and 78 genes from MDA-MB-231 and MDA-MB-468 comparisons respectively present in our published RNA-seq data. CONCLUSIONS: Using our unique model system, we have identified an isogenic gene expression signature between TNBC and HER2+ breast cancer. A portion of our results was also verified in patient data samples, indicating an existence of isogenic element associated with HER2 status between genetically heterogeneous breast cancer samples. These findings may potentially contribute to the development of molecular platform that would be valuable for diagnostic and therapeutic decision for TNBC and in distinguishing it from HER2+ subtype.

SUBMITTER: Mudvari P

PROVIDER: S-EPMC3781103 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Genomic insights into triple-negative and HER2-positive breast cancers using isogenic model systems.

Mudvari Prakriti P Ohshiro Kazufumi K Nair Vasudha V Horvath Anelia A Kumar Rakesh R

PloS one 20130923 9

<h4>Introduction</h4>In general, genomic signatures of breast cancer subtypes have little or no overlap owing to the heterogeneous genetic backgrounds of study samples. Thus, obtaining a reliable signature in the context of isogenic nature of the cells has been challenging and the precise contribution of isogenic triple negative breast cancer (TNBC) versus non-TNBC remains poorly defined.<h4>Methods</h4>We established isogenic stable cell lines representing TNBC and Human Epidermal Growth Factor ...[more]

PMID: 24086418

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Project description:One year into the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic, the 2020 San Antonio Breast Cancer Symposium (SABCS) was another large congress held in a virtual format. Despite these circumstances, clinically relevant data were presented, and this short review focuses on developments in the fields of triple-negative breast cancer (TNBC) and metastatic HER2-positive breast cancer. A quality-of-life (QoL) analysis from IMPassion031 showed that adding atezolizumab to neoadjuvant chemotherapy was not associated with a detrimental effect on QoL, while the burden of treatment-induced side effects increased with each cycle of neoadjuvant therapy in both treatment arms. KEYNOTE-355 evaluated the addition of pembrolizumab to chemotherapy as first-line treatment in metastatic TNBC (mTNBC); a significant improvement of progression-free survival (PFS) was reported in the pembrolizumab arm. At the 2020 SABCS, results with respect to different chemotherapy backbones were reported and the benefit of pembrolizumab was maintained irrespective of the type of taxane. Disappointingly, the phase III IPATunity130 study could not confirm a PFS improvement with the AKT inhibitor ipatasertib when added to paclitaxel as first-line treatment in mTNBC. A biomarker analysis from the phase III ASCENT study showed that the antibody-drug conjugate sacituzumab govitecan was superior to chemotherapy by investigator's choice independent of Trop‑2 expression and BRCA mutation status. In HER2-positive breast cancer, the PRECIOUS trial suggested a small albeit significant benefit with reinduction of pertuzumab in later treatment lines in patients progressing on prior dual HER2-blockade in the first- or second-line setting. The HER2-specific tyrosine kinase inhibitor tucatinib when added to trastuzumab and capecitabine was shown to improve PFS and overall survival (OS) over trastuzumab and capecitabine alone in pretreated patients in the randomized HER2CLIMB trial; this benefit was apparently independent of hormone-receptor expression. An update from the DESTINY-Breast01 trial reported a median PFS of 19.4 months with trastuzumab deruxtecan in heavily pretreated patients. Finally, an analysis from the PERTAIN trial with > 6 years median follow-up showed excellent OS in patients with luminal B/HER2-positive receiving first-line trastuzumab/pertuzumab in combination with endocrine therapy suggesting that chemotherapy-free treatment is an option in highly selected patients.

Dataset Information

Genomic insights into triple-negative and HER2-positive breast cancers using isogenic model systems.

Publications

Genomic insights into triple-negative and HER2-positive breast cancers using isogenic model systems.

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