Epigenetic downregulation of HER2 during EMT leads to tumor resistance to HER2-targeted therapies in breast cancer
Notice bibliographique
Résumé
ABSTRACT HER2 receptor tyrosine kinase (encoded by ERBB2 gene) is overexpressed in approximately 25% of all breast cancer tumors (known as HER2-positive breast cancers). Overexpression of HER2 causes overactivation of downstream receptor tyrosine kinase pathways including PI3K/Akt and MAPK pathways and is a poor prognosis factor in breast cancer. Tyrosine kinase inhibitor lapatinib and anti-HER2 monoclonal antibodies trastuzumab and pertuzumab are FDA-approved HER2-targeted drugs for treatment of HER2-positive breast cancers. However, development of de novo resistance to HER2 blockade occurs in majority of patients after treatment started. Resistance to HER2 targeting therapies partially due to the loss of HER2 expression on their tumor cells during the treatment. But little is known about the exact mechanism of loss of HER2 on originally HER2-positive tumor cells. Downregulation of extracellular HER2 by metalloproteinases during epithelial-mesenchymal transition (EMT) in trastuzumab-resistant/lapatinib-sensitive cells has been shown by limited studies, however, the mechanism of ERBB2 gene silencing during EMT and in the mesenchymal-like cells derived from trastuzumab-resistant/lapatinib-resistant HER2-positive breast tumors was entirely unknown. In this study, hypothesized that EMT abrogates HER2 expression by chromatin-based epigenetic silencing of ERBB2 gene as a mechanism of acquired resistance to HER2-targeted therapies. we found that HER2 expression is positively and negatively correlated with the expression of epithelial and mesenchymal phenotype marker genes respectively in breast cancer tumors. We also found that chromatin of ERBB2 gene in HER2-high epithelial-like breast cancer cells is active, while, the chromatin is inactive in HER2-low mesenchymal-like cells. HER2-low breast cancer cell line also revealed less promoter-enhancer interaction and small chromatin loops compared to the HER2-high cell lines. The lower HER2 expression, the higher EMT phenotype, and inactivated chromatin all were found correlated with a lower response to lapatinib. The higher EMT phenotype was found correlated with a lower response to lapatinib. We also found that induction of EMT of HER2-positive breast cancer BT474 cells results in downregulated HER2 expression and lower binding rate of trastuzumab to the cells. These results show that the downregulation of HER2 in mesenchymal-like cells in the culture of HER2-positive breast cancer cell lines was due to ERBB2 gene silencing by epigenetic reprogramming of the cells during EMT. These results indicate that ERBB2 gene silencing by epigenetic regulation during EMT is the main mechanism of resistance of HER2-positive breast cancer cells to trastuzumab and lapatinib.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».