@article{7d2858d256bc4e2aa05eccadd5c3bb01,
title = "Proteomic profiling identifies key coactivators utilized by mutant ERα proteins as potential new therapeutic targets",
abstract = "Approximately 75% of breast cancers are estrogen receptor alpha (ERα)-positive and are treatable with endocrine therapies, but often patients develop lethal resistant disease. Frequent mutations (10–40%) in the ligand-binding domain (LBD) codons in the gene encoding ERα (ESR1) have been identified, resulting in ligand-independent, constitutively active receptors. In addition, ESR1 chromosomal translocations can occur, resulting in fusion proteins that lack the LBD and are entirely unresponsive to all endocrine treatments. Thus, identifying coactivators that bind to these mutant ERα proteins may offer new therapeutic targets for endocrine-resistant cancer. To define coactivator candidate targets, a proteomics approach was performed profiling proteins recruited to the two most common ERα LBD mutants, Y537S and D538G, and an ESR1-YAP1 fusion protein. These mutants displayed enhanced coactivator interactions as compared to unliganded wild-type ERα. Inhibition of these coactivators decreased the ability of ESR1 mutants to activate transcription and promote breast cancer growth in vitro and in vivo. Thus, we have identified specific coactivators that may be useful as targets for endocrine-resistant breast cancers.",
author = "Gates, {Leah A.} and Guowei Gu and Yue Chen and Rohira, {Aarti D.} and Lei, {Jonathan T.} and Hamilton, {Ross A.} and Yang Yu and Lonard, {David M.} and Jin Wang and Wang, {Shu Ping} and Edwards, {David G.} and Lavere, {Philip F.} and Jiangyong Shao and Ping Yi and Antrix Jain and Jung, {Sung Yun} and Anna Malovannaya and Shunqiang Li and Jieya Shao and Roeder, {Robert G.} and Ellis, {Matthew J.} and Jun Qin and Fuqua, {Suzanne A.W.} and O{\textquoteright}Malley, {Bert W.} and Foulds, {Charles E.}",
note = "Funding Information: Acknowledgements We thank the following BCM cores (Tissue Culture, Monoclonal Antibody/Recombinant Protein and Mass Spectrometry Proteomics (funded by NCI P30 CA125123 and CPRIT RP170005), Gene Vector, Integrated Microscopy (funded by NIH (DK56338 and CA125123) and CPRIT (RP150578))), David Bader, Doug Chan, and Rainer Lanz. We acknowledge the joint participation with the Adrienne Helis Malvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with BCM and the Cancer Program. This work was supported by the NIH ((R01 HD008188 and R01 HD007857 to B. W.O.), (R01 CA207270 and R01 CA072038 to S.A.W.F), (R01 GM115622, R01 CA207701, and R21 CA213535 to J.W.), (R01 DK071900 and R01 CA178765 to R.G.R.), (1F31CA210385-01 to L. Funding Information: A.G.), and (T32 GM088129 to J.T.L.)), CPRIT ((RR140033 to M.J.E), (RP150440 and RP120732-P2 to S.A.W.F.), and (RP110784 to J.Q.)), Susan G. Komen Foundation ((PG12220321 to M.J.E.) and (CCR14300139 to Jieya Shao)), Breast Cancer Research Foundation (17-055 to S.A.W.F.), DOD ((W81XWH-13-1-0285 to B.W.O.) and (W81XWH-16-1-0539 to M.J.E.)), the Human Frontier Science Program Fellowship (LT000538/2011-L to S.P.W.), and the McNair Medical Foundation (M.J.E.). Publisher Copyright: {\textcopyright} 2018, The Author(s).",
year = "2018",
month = aug,
day = "16",
doi = "10.1038/s41388-018-0284-2",
language = "English",
volume = "37",
pages = "4581--4598",
journal = "Oncogene",
issn = "0950-9232",
number = "33",
}