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@article{Li:2022:10.1158/0008-5472.CAN-21-2576,
author = {Li, Z and Wu, Y and Yates, ME and Tasdemir, N and Bahreini, A and Chen, J and Levine, KM and Priedigkeit, NM and Nasrazadani, A and Ali, S and Buluwela, L and Arnesen, S and Gertz, J and Richer, JK and Troness, B and El-Ashry, D and Zhang, Q and Gerratana, L and Zhang, Y and Cristofanilli, M and Montanez, MA and Sundd, P and Wallace, CT and Watkins, SC and Fumagalli, C and Guerini-Rocco, E and Zhu, L and Tseng, GC and Wagle, N and Carroll, JS and Jank, P and Denkert, C and Karsten, MM and Blohmer, J-U and Park, BH and Lucas, PC and Atkinson, JM and Lee, A and Oesterreich, S},
doi = {10.1158/0008-5472.CAN-21-2576},
journal = {Cancer Research},
pages = {1321--1339},
title = {Hotspot ESR1 mutations are multimodal and contextual modulators of breast cancer metastasis},
url = {http://dx.doi.org/10.1158/0008-5472.CAN-21-2576},
volume = {82},
year = {2022}
}

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TY  - JOUR
AB  - Constitutively active estrogen receptor α (ER/ESR1) mutations have been identified in approximately one-third of ER+ metastatic breast cancers. Although these mutations are known as mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence of ESR1 mutations exclusively in distant but not local recurrences in five independent breast cancer cohorts. In concordance with transcriptomic profiling of ESR1-mutant tumors, genome-edited ESR1 Y537S and D538G-mutant cell models exhibited a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and the TIMP3/MMP axis, which functionally conferred enhanced cell–cell contacts while decreasing cell-extracellular matrix adhesion. In vivo studies showed ESR1-mutant cells were associated with larger multicellular circulating tumor cell (CTC) clusters with increased compactness compared with ESR1 wild-type CTCs. These preclinical findings translated to clinical observations, where CTC clusters were enriched in patients with ESR1-mutated metastatic breast cancer. Conversely, context-dependent migratory phenotypes revealed cotargeting of Wnt and ER as a vulnerability in a D538G cell model. Mechanistically, mutant ESR1 exhibited noncanonical regulation of several metastatic pathways, including secondary transcriptional regulation and de novo FOXA1-driven chromatin remodeling. Collectively, these data provide evidence for ESR1 mutation–modulated metastasis and suggest future therapeutic strategies for targeting ESR1-mutant breast cancer.
AU  - Li,Z
AU  - Wu,Y
AU  - Yates,ME
AU  - Tasdemir,N
AU  - Bahreini,A
AU  - Chen,J
AU  - Levine,KM
AU  - Priedigkeit,NM
AU  - Nasrazadani,A
AU  - Ali,S
AU  - Buluwela,L
AU  - Arnesen,S
AU  - Gertz,J
AU  - Richer,JK
AU  - Troness,B
AU  - El-Ashry,D
AU  - Zhang,Q
AU  - Gerratana,L
AU  - Zhang,Y
AU  - Cristofanilli,M
AU  - Montanez,MA
AU  - Sundd,P
AU  - Wallace,CT
AU  - Watkins,SC
AU  - Fumagalli,C
AU  - Guerini-Rocco,E
AU  - Zhu,L
AU  - Tseng,GC
AU  - Wagle,N
AU  - Carroll,JS
AU  - Jank,P
AU  - Denkert,C
AU  - Karsten,MM
AU  - Blohmer,J-U
AU  - Park,BH
AU  - Lucas,PC
AU  - Atkinson,JM
AU  - Lee,A
AU  - Oesterreich,S
DO  - 10.1158/0008-5472.CAN-21-2576
EP  - 1339
PY  - 2022///
SN  - 0008-5472
SP  - 1321
TI  - Hotspot ESR1 mutations are multimodal and contextual modulators of breast cancer metastasis
T2  - Cancer Research
UR  - http://dx.doi.org/10.1158/0008-5472.CAN-21-2576
UR  - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000787930700001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
UR  - https://aacrjournals.org/cancerres/article/82/7/1321/694048/Hotspot-ESR1-Mutations-Are-Multimodal-and
UR  - http://hdl.handle.net/10044/1/104315
VL  - 82
ER  -

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