TY - JOUR
T1 - A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer
AU - Nardone, Agostina
AU - Qiu, Xintao
AU - Spisak, Sandor
AU - Nagy, Zsuzsanna
AU - Feiglin, Ariel
AU - Feit, Avery
AU - Feit, Gabriela Cohen
AU - Xie, Yingtian
AU - Font-Tello, Alba
AU - Guarducci, Cristina
AU - Hermida-Prado, Francisco
AU - Syamala, Sudeepa
AU - Lim, Klothilda
AU - Gomez, Miguel Munoz
AU - Pun, Matthew
AU - Cornwell, MacIntosh
AU - Liu, Weihan
AU - Ors, Aysegul
AU - Mohammed, Hisham
AU - Cejas, Paloma
AU - Brock, Jane B.
AU - Freedman, Matthew L.
AU - Winer, Eric P.
AU - Fu, Xiaoyong
AU - Schiff, Rachel
AU - Long, Henry W.
AU - Filho, Otto Metzger
AU - Jeselsohn, Rinath
N1 - Funding Information:
M.L. Freedman reports personal fees and other support from Precede outside the submitted work. R. Schiff reports grants from Breast Cancer Research Foundation during the conduct of the study; grants from Gilead Sciences, Puma, Biotechnology Inc, personal fees from Macrogenics, and Wolters Kluwer/UpToDate outside the submitted work; and reports a pending patent (via institution), which is truly unrelated to the currently submitted work, but is still disclosed below: NRF Ref. BAYM.P0312US.P1-1001123973: “A multiparameter classifier to predict response to HER2-targeted therapy without chemotherapy in HER2-positive breast cancer.” No revenue was received. R. Jeselsohn reports other support from Pfizer and grants from Lilly during the conduct of the study; personal fees from Luminex and other support from Pfizer outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
This work was conducted with support from the Maor Foundation (to E. Winer, O. Metzger Filho, and R. Jeselsohn) and NIH (5RO1CA237414-02 and 1K08CA191058-01A1 to R. Jeselsohn; 5RO1CA193910-03 to M.L. Freedman). The authors thank Ms. Cheri Fox for her support, important insights, and helpful discussion.
Publisher Copyright:
© 2022 American Association for Cancer Research Inc.. All rights reserved.
PY - 2022/10/15
Y1 - 2022/10/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-21-3186
DO - 10.1158/0008-5472.CAN-21-3186
M3 - Article
C2 - 35950920
AN - SCOPUS:85140144725
SN - 0008-5472
VL - 82
SP - 3673
EP - 3686
JO - Cancer Research
JF - Cancer Research
IS - 20
ER -