ShcA is an integrator of ErbB2 and TGFÃ signaling pathway interactions in Breast Cancer
Notice bibliographique
Résumé
The ErbB2 and TGFβ signaling pathways cooperate to promote breast cancer progression and metastasis. The formation of distant metastases is the leading cause of mortality for breast cancer patients. To identify the mechanisms underlying the synergy between ErbB2 and TGFβ pathways, we transformed mammary epithelial cells with a panel of activated ErbB2 receptors, in which specific autophosphorylation sites that initiate distinct signaling pathways were mutated. We determined tyrosine residues 1226/1227 and 1253 within the ErbB2 receptor are required for TGFβ-induced migration and invasion of breast cancer cells. Using transient knockdown approaches, we subsequently demonstrated that ShcA was required downstream of these tyrosine residues for these TGFβ-mediated effects. In addition, TGFβ stimulation of ErbB2-expressing breast cancer cells with diminished ShcA expression resulted in the formation of larger and more numerous focal adhesions. These results indicated that signaling through ShcA is required for the TGFβ-induced formation of pro-migratory, dynamic focal adhesions in ErbB2-expressing cells. To investigate a requirement for ShcA signaling in the promotion of tumor progression and metastasis in vivo, we generated ErbB2-expressing breast cancer cells with a stable shRNA-mediated knockdown of ShcA expression. Diminished ShcA expression impaired tumor growth and spontaneous metastasis. Immunohistochemical staining revealed that loss of ShcA signaling results in decreased tumor proliferation and endothelial cell recruitment, coupled with an increase in apoptosis. Rescue experiments with wild-type ShcA or a panel of ShcA functional domain mutants revealed that the PTB-domain and three tyrosine residues (239/240 and 313) were necessary for TGFβ-induced migration and invasion. The Grb2 and Crk adaptor proteins have been implicated in signaling downstream of these ShcA tyrosine residues. A transient knockdown of these adaptors uncovered specific roles for Grb2 downstream of ShcA Y313 and the Crk adaptors downstream of ShcA Y239/240 for TGFβ-induced effects. An investigation of the significance of these ShcA tyrosine sites for tumor growth in vivo demonstrated that ShcA signaling through Y313 enhances tumor cell survival while signaling through ShcA Y239/240 promotes the recruitment of endothelial cells. Finally, we employed an inducible knockdown of ShcA to identify acute TGFβ-induced gene expression changes in ErbB2-expressing cells that depend on ShcA expression. We identified numerous candidate genes that were regulated by TGFβ in a ShcA-dependent manner, including the BMP antagonist, Chordin-like 1. We confirmed that reduced ShcA signaling results in the up-regulation of secreted Chordin-like 1 protein in ErbB2-expressing cells following TGFβ stimulation. Functional roles for Chordin-like 1 in ErbB2-driven tumor growth, survival and angiogenesis are currently being investigated.The work described in this thesis is the first to identify ShcA as an integral mediator underlying the cooperation between the ErbB2 and TGFβ signaling pathways in breast cancer progression and to define molecular mechanisms through which ShcA functions in this context.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 ».