A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer

Agostina Nardone, Xintao Qiu, Sandor Spisak, Zsuzsanna Nagy, Ariel Feiglin, Avery Feit, Gabriela Cohen Feit, Yingtian Xie, Alba Font-Tello, Cristina Guarducci, Francisco Hermida-Prado, Sudeepa Syamala, Klothilda Lim, Miguel Munoz Gomez, Matthew Pun, MacIntosh Cornwell, Weihan Liu, Aysegul Ors, Hisham Mohammed, Paloma CejasJane B. Brock, Matthew L. Freedman, Eric P. Winer, Xiaoyong Fu, Rachel Schiff, Henry W. Long, Otto Metzger Filho, Rinath Jeselsohn

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3673-3686
Number of pages14
JournalCancer Research
Issue number20
StatePublished - Oct 15 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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