A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
17 10 2022
17 10 2022
Historique:
received:
20
09
2021
revised:
04
02
2022
accepted:
09
08
2022
pubmed:
12
8
2022
medline:
19
10
2022
entrez:
11
8
2022
Statut:
ppublish
Résumé
Most invasive lobular breast cancers (ILC) are of the luminal A subtype and are strongly hormone receptor-positive. Yet, ILC is relatively resistant to tamoxifen and associated with inferior long-term outcomes compared with invasive ductal cancers (IDC). In this study, we sought to gain mechanistic insights into these clinical findings that are not explained by the genetic landscape of ILC and to identify strategies to improve patient outcomes. A comprehensive analysis of the epigenome of ILC in preclinical models and clinical samples showed that, compared with IDC, ILC harbored a distinct chromatin state linked to gained recruitment of FOXA1, a lineage-defining pioneer transcription factor. This resulted in an ILC-unique FOXA1-estrogen receptor (ER) axis that promoted the transcription of genes associated with tumor progression and poor outcomes. The ILC-unique FOXA1-ER axis led to retained ER chromatin binding after tamoxifen treatment, which facilitated tamoxifen resistance while remaining strongly dependent on ER signaling. Mechanistically, gained FOXA1 binding was associated with the autoinduction of FOXA1 in ILC through an ILC-unique FOXA1 binding site. Targeted silencing of this regulatory site resulted in the disruption of the feed-forward loop and growth inhibition in ILC. In summary, ILC is characterized by a unique chromatin state and FOXA1-ER axis that is associated with tumor progression, offering a novel mechanism of tamoxifen resistance. These results underscore the importance of conducting clinical trials dedicated to patients with ILC in order to optimize treatments in this breast cancer subtype. A unique FOXA1-ER axis in invasive lobular breast cancer promotes disease progression and tamoxifen resistance, highlighting a potential therapeutic avenue for clinical investigations dedicated to this disease. See related commentary by Blawski and Toska, p. 3668.
Identifiants
pubmed: 35950920
pii: 707656
doi: 10.1158/0008-5472.CAN-21-3186
pmc: PMC9588703
mid: NIHMS1830937
doi:
Substances chimiques
Chromatin
0
Receptors, Estrogen
0
Tamoxifen
094ZI81Y45
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3673-3686Subventions
Organisme : NCI NIH HHS
ID : K08 CA191058
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA250959
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA237414
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193910
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2022 American Association for Cancer Research.
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