Abstract 5013: Loss of Igfbp7 leads to the expansion of luminal progenitors by altering the stromal fibroblasts’ ability to support luminal cell differentiation.
Notice bibliographique
Résumé
Abstract Insulin-like growth factor binding protein 7, IGFBP7, is a secreted glycoprotein that unlike other IGFBPs, binds insulin with higher affinity than IGFs. Interestingly, high-grade invasive breast cancers lack IGFBP7 expression, and its low expression levels is associated with reduced patient survival. Interestingly, in some cancers expression of IGFBP7 is lost due to promoter methylation or loss of hetrozygosity. Also, in vivo xenograft assays have shown that IGFBP7 can suppress breast cancer cell proliferation. These data together imply that IGFBP7 may act as a potential tumor suppressor. Recent evidence suggests that tumor suppressors and oncogenes play essential roles in regulating the normal development of mammary gland and that alterations to their expression or functions may transform the undifferentiated breast stem cells and progenitors into cancer initiating cells. To examine if IGFBP7 plays essential roles in regulating the normal development of the mammary gland, we developed Igfbp7-null mice and examine the development of the mammary glands. Notably, the pre- and post-pubertal Igfbp7-null glands featured decreased overall size and diminished terminal end bud and alveolar densities. However, the Igfbp7-null glands showed the most startling defects during pregnancy and lactation where lobular sacs were severely deformed and decreased in numbers. To ascertain the molecular mechanism underlying this defective lobular development, we compared the transcriptome profiles of the Igfbp7-null glands and the Wild-Type (WT) glands using RNA-Seq technology. Our transcriptome analysis revealed the decreased expression of a number of key signaling molecules involved in the Notch and IGF/Insulin and other signaling pathways. Interestingly our analysis also revealed the decreased expression of luminal cell differentiation-associated genes such as Gata3 and Pml. Through quantifying, for the first time, the number of luminal progenitors during the different phases of pregnancy and lactation, we determined that loss of Igfbp7 lead to the increased frequency (up to 5±0.3 folds) and thusly, yield (up to 3±0.25 folds) of the luminal progenitors and yet these Igfbp7-null progenitors are unable to differentiate in vivo. We further show that the Igfbp7-null stromal fibroblasts are unable to support the differentiation of the luminal progenitors. For the first time we demonstrate that loss of a tumor suppressor gene, Igfbp7, can suppress the ability of luminal progenitors to differentiate by altering the properties of stromal fibroblasts. It is interesting that the loss of a tumor suppressor gene would result in the expansion of the luminal progenitors since these progenitors and other undifferentiated cells have been envisaged to be prime cellular targets to accumulate transforming mutations that can cause them to act as cancer initiating cells. Citation Format: Sumanta Chatterjee, Stephanie Bacopulos, WenYi Yang, Yutaka Amemiya, Demetri Spyropoulos, Arun Seth, Afshin Raouf. Loss of Igfbp7 leads to the expansion of luminal progenitors by altering the stromal fibroblasts’ ability to support luminal cell differentiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5013. doi:10.1158/1538-7445.AM2013-5013
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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,001 |
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 ».