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 Cejas; Jane B. Brock; Matthew L. Freedman; Eric P. Winer; Xiaoyong Fu; Rachel Schiff; Henry W. Long; Otto Metzger Filho; Rinath Jeselsohn

doi:10.1158/0008-5472.CAN-21-3186

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 journal › Article › peer-review

8 Scopus citations

Abstract

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 language	English
Pages (from-to)	3673-3686
Number of pages	14
Journal	Cancer Research
Volume	82
Issue number	20
DOIs	https://doi.org/10.1158/0008-5472.CAN-21-3186
State	Published - 17 Oct 2022
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2022 American Association for Cancer Research Inc.. All rights reserved.

Funding

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. 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.

Funders	Funder number
Maor Foundation
National Institutes of Health	5RO1CA193910-03, 1K08CA191058-01A1
National Cancer Institute	R01CA237414
Breast Cancer Research Foundation
Pfizer
Gilead Sciences	BAYM.P0312US.P1-1001123973

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/0008-5472.CAN-21-3186

Cite this

Nardone, A., Qiu, X., Spisak, S., Nagy, Z., Feiglin, A., Feit, A., Feit, G. C., Xie, Y., Font-Tello, A., Guarducci, C., Hermida-Prado, F., Syamala, S., Lim, K., Gomez, M. M., Pun, M., Cornwell, M., Liu, W., Ors, A., Mohammed, H., ... Jeselsohn, R. (2022). A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer. Cancer Research, 82(20), 3673-3686. https://doi.org/10.1158/0008-5472.CAN-21-3186

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title = "A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer",

abstract = "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.",

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

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doi = "10.1158/0008-5472.CAN-21-3186",

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Nardone, A, Qiu, X, Spisak, S, Nagy, Z, Feiglin, A, Feit, A, Feit, GC, Xie, Y, Font-Tello, A, Guarducci, C, Hermida-Prado, F, Syamala, S, Lim, K, Gomez, MM, Pun, M, Cornwell, M, Liu, W, Ors, A, Mohammed, H, Cejas, P, Brock, JB, Freedman, ML, Winer, EP, Fu, X, Schiff, R, Long, HW, Filho, OM & Jeselsohn, R 2022, 'A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer', Cancer Research, vol. 82, no. 20, pp. 3673-3686. https://doi.org/10.1158/0008-5472.CAN-21-3186

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

PY - 2022/10/17

Y1 - 2022/10/17

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

Abstract

Bibliographical note

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