Abstract P2-06-03: Obesity is associated with DNA damage in the breast epithelium of BRCA1 and BRCA2 mutation carriers: A role for estrogens & strategies for prevention
Notice bibliographique
Résumé
Abstract Background: Elevated bodyweight is a risk factor for breast cancer development in women who carry a mutation in the DNA repair enzymes BRCA1 and BRCA2. However, the mechanistic basis for this association is unknown. Breast adipose tissue undergoes significant changes in the setting of weight gain and obesity, including elevation in aromatase expression which leads to the increased biosynthesis of estrogens. Given that estrogens and estrogen metabolites have known pro-proliferative and genotoxic effects, we hypothesized that in BRCA1/2 mutation carriers, obesity may be positively associated with breast epithelial cell DNA damage, thereby increasing the risk of tumorigenesis. Furthermore, we examined the impact of inhibiting estrogen signaling or production on breast epithelium DNA damage in BRCA1/2 mutation carriers. Methods: Tissue microarrays were generated from non-cancerous breast tissue derived from 72 women carrying a mutation in BRCA1 or BRCA2 with known body mass index (BMI, kg/m2). Breast epithelium DNA damage was quantified by immunofluorescence (IF) staining of the DNA damage marker γH2AX. RNA-Seq was performed on breast organoids to assess differences in gene expression in relation to BMI. Associations between DNA damage and biomarkers of estrogen biosynthesis and bioavailability, including aromatase expression in the breast and circulating steroid hormone binding globulin (SHBG), were also evaluated. To explore the effect of blocking estrogen signaling or production on DNA damage, non-tumorous breast tissue explants from BRCA1/2 mutation carriers were cultured with fulvestrant, an estrogen receptor degrader, or metformin, an anti-diabetic drug that also reduces aromatase expression in the breast. Breast epithelial cell DNA damage was measured in control vs treated explants by γH2AX IF staining after 24 hours of treatment. Results: BMI was positively correlated with DNA damage in the breast epithelium of BRCA1/2 mutation carriers. Upstream analysis of gene expression in organoids derived from women with a BMI ≥ 30 compared to <25, revealed activation of estrogen signaling. Further supporting a contribution of locally-derived and circulating estrogens to obesity-related DNA damage, breast aromatase expression was found to be positively correlated with DNA damage while circulating SHBG levels showed a negative correlation. Targeting estrogen signaling with fulvestrant significantly reduced breast epithelium DNA damage in breast explants from women carrying a mutation in either BRCA1 or BRCA2. Interestingly, metformin, also caused a significant reduction in DNA damage in breast explants. Conclusion: These data provide mechanistic evidence for the link between obesity and breast cancer in BRCA1 and BRCA2 mutation carriers through identification of a positive association between BMI and breast epithelial cell DNA damage. Importantly, these studies demonstrate that fulvestrant and metformin, drugs already approved for clinical use, decrease breast epithelial cell DNA damage. Further studies are warranted to determine whether targeting estrogens or use of metformin may be effective risk reduction strategies in BRCA1/2 mutation carriers with excess bodyweight who are at high risk for breast cancer development and currently have limited options for prevention beyond surgical intervention. Support: NIH R01CA215797, NIH F31CA236306, Anne Moore Breast Cancer Research Fund Citation Format: Priya Bhardwaj, Neil M. Iyengar, Sofya Oshchepkova, Phoebe Piloco, Rohan Bareja, Olivier Elemento, Dilip D. Giri, Michael Pollak, Monica Morrow, Jason A. Spector, Kristy A. Brown. Obesity is associated with DNA damage in the breast epithelium of BRCA1 and BRCA2 mutation carriers: A role for estrogens & strategies for prevention [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-06-03.
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) | 0,006 | 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 ».