Abstract P5-11-04: Inhibition of alternative NF-κB activity prevents the expansion of genetically unstable progenitor cells in BRCA1-deficient mammary glands
Notice bibliographique
Résumé
Abstract Understanding the biological mechanisms underlying the initiation and progression of breast cancer is an important step for prevention and treatment. Individuals with mutations in the breast cancer-associated gene 1 (BRCA1) have a lifetime increased risk of up to 85% of developing breast cancer. BRCA1 participates in DNA damage repair and cell cycle checkpoint control, serving as a tumor suppressor gene to maintain global genomic stability. However, BRCA1 has also been shown to play a key role in the expansion of mammary stem/progenitor cells, which are the targets for carcinogenesis in individuals who have undergone loss of heterozygosity (LOH) for BRCA1. We have used in vitro and in vivo models to demonstrate that BRCA1 loss or mutation induces alternative NF-κB pathway activation and leads to the expansion of a genetically unstable progenitor cell population in the mammary gland. Our data showed that BRCA1 loss or mutation is responsible for activation of the alternative NF-κB pathway evidenced by IκB kinase-α (IKKα) phosphorylation, processing of p100 to p52 and p52/RelB nuclear localization. Remarkably, we found that RelB and p100/p52 were highly expressed in 20-50% of the lobular structures in histologically normal breast tissue obtained from human BRCA1 mutation carriers. After DNA damage, ATM directs the nuclear export of NEMO (NF-κB essential modifier) that in turn activates the alternative NF-κB pathway. We found high levels of phospho-ATM in breast tissue from human BRCA1-mutation carriers and in progenitor cells from BRCA1-knockout mouse mammary glands. Moreover, co-immunoprecipitation studies showed increased ATM/NEMO-containing complexes in BRCA1-deficient cells. Progesterone injections into MMTV-cre;BRCA1f/f mice induced an increase in Ki-67 and phospho-H2AX levels, demonstrating a role for progesterone in DNA damage amplification in mouse mammary glands. Mammary epithelial progenitor cells obtained from BRCA1-mutated carriers as well as BRCA1-/- mouse glands can form acini in Matrigel in a progesterone-independent manner. We found that in vivo inhibition of IKKα/β using the IKK inhibitor dimethylaminoparthenolide (DMAPT) completely blocked mammary acini formation in Matrigel, requiring several estrus cycles post-injection to recover. Importantly, knockdown studies showed that p100/p52 was necessary for progenitor cell proliferation in Matrigel. Consistent with the continued dependence on alternative NF-κB activity in tumors derived from BRCA1-deficient progenitor cells, human breast cancer xenografts derived from BRCA1-mutation carriers infected with lenti-shp100/p52 showed a significant growth inhibition. Overall, these results suggest an exciting new approach for the prevention of breast cancer in patients wherein intermittent or cyclic therapy using DMAPT (generic name LC-1) has the potential to mitigate breast cancer risk in BRCA1 mutation carriers through acute reduction of aberrant progenitor activity. As such, NF-κB-directed chemopreventive therapies may provide promising alternatives to prophylactic mastectomy in this high risk patient population. Citation Format: Andrea Sau, Rosanna Lau, Emma Nolan, Peter A Crooks, Jane E Visvader, Christine MA Pratt. Inhibition of alternative NF-κB activity prevents the expansion of genetically unstable progenitor cells in BRCA1-deficient mammary glands [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-11-04.
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) | 0,005 | 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 ».