High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer

Xiaoyong Fu; Resel Pereira; Chia Chia Liu; Carmine De Angelis; Martin J. Shea; Sarmistha Nanda; Lanfang Qin; Tamika Mitchell; Maria L. Cataldo; Jamunarani Veeraraghavan; Vidyalakshmi Sethunath; Mario Giuliano; Carolina Gutierrez; Balázs Győrffy; Meghana V. Trivedi; Ofir Cohen; Nikhil Wagle; Agostina Nardone; Rinath Jeselsohn; Mothaffar F. Rimawi; C. Kent Osborne; Rachel Schiff

doi:10.1016/j.celrep.2023.112821

High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer

Xiaoyong Fu, Resel Pereira, Chia Chia Liu, Carmine De Angelis, Martin J. Shea, Sarmistha Nanda, Lanfang Qin, Tamika Mitchell, Maria L. Cataldo, Jamunarani Veeraraghavan, Vidyalakshmi Sethunath, Mario Giuliano, Carolina Gutierrez, Balázs Győrffy, Meghana V. Trivedi, Ofir Cohen, Nikhil Wagle, Agostina Nardone, Rinath Jeselsohn, Mothaffar F. RimawiC. Kent Osborne, Rachel Schiff

The Shraga Segal Department of Microbiology and Immunology

Research output: Contribution to journal › Article › peer-review

Abstract

Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, the key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) enriched in ER+ endocrine-resistant (EndoR) cells. We identify Secretome14, a CGS subset encoding ER-dependent cancer secretory proteins, as a strong predictor for poor outcomes of ER+ BC. It is elevated in ER+ metastases vs. primary tumors, irrespective of ESR1 mutations. Genomic ER binding near Secretome14 genes is also increased in mutant ER-expressing or mitogen-treated ER+ BC cells and in ER+ metastatic vs. primary tumors, suggesting a convergent pathway including high growth factor receptor signaling in activating pro-metastatic secretome genes. Our findings uncover H-FOXA1-induced ER reprogramming that drives EndoR and metastasis partly via an H-FOXA1/ER-dependent secretome.

Original language	English
Article number	112821
Journal	Cell Reports
Volume	42
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2023.112821
State	Published - 29 Aug 2023

Keywords

CP: Cancer
breast cancer
cistrome
endocrine resistance
enhancer
epigenetic
estrogen receptor
forkhead box protein A1
metastasis
secretome
transcription factor

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

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

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10.1016/j.celrep.2023.112821

Cite this

Fu, X., Pereira, R., Liu, C. C., De Angelis, C., Shea, M. J., Nanda, S., Qin, L., Mitchell, T., Cataldo, M. L., Veeraraghavan, J., Sethunath, V., Giuliano, M., Gutierrez, C., Győrffy, B., Trivedi, M. V., Cohen, O., Wagle, N., Nardone, A., Jeselsohn, R., ... Schiff, R. (2023). High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer. Cell Reports, 42(8), Article 112821. https://doi.org/10.1016/j.celrep.2023.112821

@article{cb179ad153e84d278d3f66682ed900fe,

title = "High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer",

abstract = "Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, the key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) enriched in ER+ endocrine-resistant (EndoR) cells. We identify Secretome14, a CGS subset encoding ER-dependent cancer secretory proteins, as a strong predictor for poor outcomes of ER+ BC. It is elevated in ER+ metastases vs. primary tumors, irrespective of ESR1 mutations. Genomic ER binding near Secretome14 genes is also increased in mutant ER-expressing or mitogen-treated ER+ BC cells and in ER+ metastatic vs. primary tumors, suggesting a convergent pathway including high growth factor receptor signaling in activating pro-metastatic secretome genes. Our findings uncover H-FOXA1-induced ER reprogramming that drives EndoR and metastasis partly via an H-FOXA1/ER-dependent secretome.",

keywords = "CP: Cancer, breast cancer, cistrome, endocrine resistance, enhancer, epigenetic, estrogen receptor, forkhead box protein A1, metastasis, secretome, transcription factor",

author = "Xiaoyong Fu and Resel Pereira and Liu, {Chia Chia} and {De Angelis}, Carmine and Shea, {Martin J.} and Sarmistha Nanda and Lanfang Qin and Tamika Mitchell and Cataldo, {Maria L.} and Jamunarani Veeraraghavan and Vidyalakshmi Sethunath and Mario Giuliano and Carolina Gutierrez and Bal{\'a}zs Gy{\H o}rffy and Trivedi, {Meghana V.} and Ofir Cohen and Nikhil Wagle and Agostina Nardone and Rinath Jeselsohn and Rimawi, {Mothaffar F.} and Osborne, {C. Kent} and Rachel Schiff",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = aug,

day = "29",

doi = "10.1016/j.celrep.2023.112821",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "8",

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Fu, X, Pereira, R, Liu, CC, De Angelis, C, Shea, MJ, Nanda, S, Qin, L, Mitchell, T, Cataldo, ML, Veeraraghavan, J, Sethunath, V, Giuliano, M, Gutierrez, C, Győrffy, B, Trivedi, MV, Cohen, O, Wagle, N, Nardone, A, Jeselsohn, R, Rimawi, MF, Osborne, CK & Schiff, R 2023, 'High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer', Cell Reports, vol. 42, no. 8, 112821. https://doi.org/10.1016/j.celrep.2023.112821

TY - JOUR

T1 - High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer

AU - Fu, Xiaoyong

AU - Pereira, Resel

AU - Liu, Chia Chia

AU - De Angelis, Carmine

AU - Shea, Martin J.

AU - Nanda, Sarmistha

AU - Qin, Lanfang

AU - Mitchell, Tamika

AU - Cataldo, Maria L.

AU - Veeraraghavan, Jamunarani

AU - Sethunath, Vidyalakshmi

AU - Giuliano, Mario

AU - Gutierrez, Carolina

AU - Győrffy, Balázs

AU - Trivedi, Meghana V.

AU - Cohen, Ofir

AU - Wagle, Nikhil

AU - Nardone, Agostina

AU - Jeselsohn, Rinath

AU - Rimawi, Mothaffar F.

AU - Osborne, C. Kent

AU - Schiff, Rachel

PY - 2023/8/29

Y1 - 2023/8/29

N2 - Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, the key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) enriched in ER+ endocrine-resistant (EndoR) cells. We identify Secretome14, a CGS subset encoding ER-dependent cancer secretory proteins, as a strong predictor for poor outcomes of ER+ BC. It is elevated in ER+ metastases vs. primary tumors, irrespective of ESR1 mutations. Genomic ER binding near Secretome14 genes is also increased in mutant ER-expressing or mitogen-treated ER+ BC cells and in ER+ metastatic vs. primary tumors, suggesting a convergent pathway including high growth factor receptor signaling in activating pro-metastatic secretome genes. Our findings uncover H-FOXA1-induced ER reprogramming that drives EndoR and metastasis partly via an H-FOXA1/ER-dependent secretome.

AB - Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, the key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) enriched in ER+ endocrine-resistant (EndoR) cells. We identify Secretome14, a CGS subset encoding ER-dependent cancer secretory proteins, as a strong predictor for poor outcomes of ER+ BC. It is elevated in ER+ metastases vs. primary tumors, irrespective of ESR1 mutations. Genomic ER binding near Secretome14 genes is also increased in mutant ER-expressing or mitogen-treated ER+ BC cells and in ER+ metastatic vs. primary tumors, suggesting a convergent pathway including high growth factor receptor signaling in activating pro-metastatic secretome genes. Our findings uncover H-FOXA1-induced ER reprogramming that drives EndoR and metastasis partly via an H-FOXA1/ER-dependent secretome.

KW - CP: Cancer

KW - breast cancer

KW - cistrome

KW - endocrine resistance

KW - enhancer

KW - epigenetic

KW - estrogen receptor

KW - forkhead box protein A1

KW - metastasis

KW - secretome

KW - transcription factor

UR - http://www.scopus.com/inward/record.url?scp=85166638196&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2023.112821

DO - 10.1016/j.celrep.2023.112821

M3 - Article

C2 - 37467106

AN - SCOPUS:85166638196

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 8

M1 - 112821

ER -

High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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