Abstract 322: Distinct pools of ShcA coupled tyrosine kinase signaling influences breast tumor heterogeneity and therapeutic responsiveness
Notice bibliographique
Résumé
Abstract Phospho-tyrosine (pTyr) signaling networks are frequently activated in breast cancers (BrCa) and are considered to be major oncogenic drivers of tumor progression. Therapeutic interventions, such as the tyrosine kinase (TK) inhibitor Trastuzumab, focus on targeting TK activity and downstream effectors. Although successful for early stage tumors, a subset of patients experience relapse due to intrinsic or acquired resistance. This includes activation of alternative receptor tyrosine kinase (RTK) and/or cytoplasmic TKs, many of which require recruitment of the adaptor protein, ShcA. ShcA is a key convergence point downstream of RTKs and serves to integrate multiple signal transduction pathways dysregulated in BrCa. Specifically, ShcA contains two pTyr binding motifs including an amino-terminal PTB domain and a carboxy-terminal SH2 domain which facilitate its interactions with TKs including ErbB2 and Src Family Kinases (SFK), respectively. The CH-1 domain houses three tyrosine phosphorylation sites at residues 239/240 and 317 which transduce Ras-dependent and independent signals. Using a well characterized transgenic mouse model of BrCa where ShcA can no longer engage the transforming oncogene through its PTB domain, we demonstrate that loss of PTB-driven ShcA (ShcA-PTBMut) signaling delays mammary tumor onset. However, once formed, the growth and angiogenic potential of these tumors is significantly increased relative to control mice. Increased growth potential of ShcA-PTBMut tumors is associated with the hyper-activation of the c-Src tyrosine kinase. Deletion of c-Src in ShcA-PTBMut breast tumor cells significantly delays tumor onset but is dispensable for the growth of tumors that retain an intact ShcA PTB domain. These data suggest that the ShcA PTB domain can recruit negative regulators that limit the activation of downstream tumorigenic signaling networks. Interestingly, tumors expressing ShcA-PTBMut debilitated in SH2 driven pTyr interactions (SH2Mut), are significantly delayed in tumor onset relative to ShcA-PTBMut controls. Paradoxically, deletion of c-Src in the context of ShcA-PTBMut-SH2Mut further accelerates tumor growth which is attributed to increased levels of Fyn and Lyn. These observations support the high dependence of intracellular ShcA pools on other SFK family members to retain tumorigenic potential when adapting to low levels and/or activity of c-Src. We demonstrate that uncoupling of PTB-driven ShcA signaling from upstream RTKs can potentiate ShcA signaling from intracellular pools to hyper-activate SFKs. This data is clinically relevant as c-Src is frequently hyper-activated in Trastuzumab-resistant BrCa. This is the first study to identify a tumor suppressive role of the ShcA PTB domain and to characterize an intrinsic ShcA SH2 domain-SFK dependent resistance mechanism downstream of activated RTKs in mammary tumorigenesis. Citation Format: Jacqueline R. Ha, Ryuhjin Ahn, Young Kyuen Im, Valerie Sabourin, Harvey W. Smith, Ivan Topisirovic, Tony Pawson, Peter Siegel, William J. Muller, Josie Ursini-Siegel. Distinct pools of ShcA coupled tyrosine kinase signaling influences breast tumor heterogeneity and therapeutic responsiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 322. doi:10.1158/1538-7445.AM2017-322
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) | 0,003 | 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 ».