Therapeutic role of recurrent ESR1-CCDC170 gene fusions in breast cancer endocrine resistance.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Breast Neoplasms
/ drug therapy
Carrier Proteins
/ genetics
Cell Line, Tumor
Dasatinib
/ administration & dosage
Drug Resistance, Neoplasm
Estrogen Receptor alpha
/ genetics
Female
Fulvestrant
/ administration & dosage
Humans
Lapatinib
/ administration & dosage
Mice
Mice, Nude
Oncogene Proteins, Fusion
Receptor, ErbB-2
/ antagonists & inhibitors
Signal Transduction
Tamoxifen
/ administration & dosage
Xenograft Model Antitumor Assays
src-Family Kinases
/ antagonists & inhibitors
ESR1-CCDC170
Endocrine resistance
HER2
Luminal breast cancer
SRC
Journal
Breast cancer research : BCR
ISSN: 1465-542X
Titre abrégé: Breast Cancer Res
Pays: England
ID NLM: 100927353
Informations de publication
Date de publication:
08 08 2020
08 08 2020
Historique:
received:
15
10
2019
accepted:
27
07
2020
entrez:
11
8
2020
pubmed:
11
8
2020
medline:
14
1
2021
Statut:
epublish
Résumé
Endocrine therapy is the most common treatment for estrogen receptor (ER)-positive breast cancer, but its effectiveness is limited by high rates of primary and acquired resistance. There are likely many genetic causes, and recent studies suggest the important role of ESR1 mutations and fusions in endocrine resistance. Previously, we reported a recurrent ESR1 fusion called ESR1-CCDC170 in 6-8% of the luminal B breast cancers that has a worse clinical outcome after endocrine therapy. Despite being the most frequent ESR1 fusion, its functional role in endocrine resistance has not been studied in vivo, and the engaged mechanism and therapeutic relevance remain uncharacterized. The endocrine sensitivities of HCC1428 or T47D breast cancer cells following genetic perturbations of ESR1-CCDC170 were assessed using clonogenic assays and/or xenograft mouse models. The underlying mechanisms were investigated by reverse phase protein array, western blotting, immunoprecipitation, and bimolecular fluorescence complementation assays. The sensitivity of ESR1-CCDC170 expressing breast cancer cells to concomitant treatments of tamoxifen and HER/SRC inhibitors was assessed by clonogenic assays. Our results suggested that different ESR1-CCDC170 fusions endow different levels of reduced endocrine sensitivity in vivo, resulting in significant survival disadvantages. Further investigation revealed a novel mechanism that ESR1-CCDC170 binds to HER2/HER3/SRC and activates SRC/PI3K/AKT signaling. Silencing of ESR1-CCDC170 in the fusion-positive cell line, HCC1428, downregulates HER2/HER3, represses pSRC/pAKT, and improves endocrine sensitivity. More important, breast cancer cells expressing ectopic or endogenous ESR1-CCDC170 are highly sensitive to treatment regimens combining endocrine agents with the HER2 inhibitor lapatinib and/or the SRC inhibitor dasatinib. ESR1-CCDC170 may endow breast cancer cell survival under endocrine therapy via maintaining/activating HER2/HER3/SRC/AKT signaling which implies a potential therapeutic strategy for managing these fusion positive tumors.
Sections du résumé
BACKGROUND
Endocrine therapy is the most common treatment for estrogen receptor (ER)-positive breast cancer, but its effectiveness is limited by high rates of primary and acquired resistance. There are likely many genetic causes, and recent studies suggest the important role of ESR1 mutations and fusions in endocrine resistance. Previously, we reported a recurrent ESR1 fusion called ESR1-CCDC170 in 6-8% of the luminal B breast cancers that has a worse clinical outcome after endocrine therapy. Despite being the most frequent ESR1 fusion, its functional role in endocrine resistance has not been studied in vivo, and the engaged mechanism and therapeutic relevance remain uncharacterized.
METHODS
The endocrine sensitivities of HCC1428 or T47D breast cancer cells following genetic perturbations of ESR1-CCDC170 were assessed using clonogenic assays and/or xenograft mouse models. The underlying mechanisms were investigated by reverse phase protein array, western blotting, immunoprecipitation, and bimolecular fluorescence complementation assays. The sensitivity of ESR1-CCDC170 expressing breast cancer cells to concomitant treatments of tamoxifen and HER/SRC inhibitors was assessed by clonogenic assays.
RESULTS
Our results suggested that different ESR1-CCDC170 fusions endow different levels of reduced endocrine sensitivity in vivo, resulting in significant survival disadvantages. Further investigation revealed a novel mechanism that ESR1-CCDC170 binds to HER2/HER3/SRC and activates SRC/PI3K/AKT signaling. Silencing of ESR1-CCDC170 in the fusion-positive cell line, HCC1428, downregulates HER2/HER3, represses pSRC/pAKT, and improves endocrine sensitivity. More important, breast cancer cells expressing ectopic or endogenous ESR1-CCDC170 are highly sensitive to treatment regimens combining endocrine agents with the HER2 inhibitor lapatinib and/or the SRC inhibitor dasatinib.
CONCLUSION
ESR1-CCDC170 may endow breast cancer cell survival under endocrine therapy via maintaining/activating HER2/HER3/SRC/AKT signaling which implies a potential therapeutic strategy for managing these fusion positive tumors.
Identifiants
pubmed: 32771039
doi: 10.1186/s13058-020-01325-3
pii: 10.1186/s13058-020-01325-3
pmc: PMC7414578
doi:
Substances chimiques
CCDC170 protein, human
0
Carrier Proteins
0
ESR1 protein, human
0
Estrogen Receptor alpha
0
Oncogene Proteins, Fusion
0
Tamoxifen
094ZI81Y45
Lapatinib
0VUA21238F
Fulvestrant
22X328QOC4
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
src-Family Kinases
EC 2.7.10.2
Dasatinib
RBZ1571X5H
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
84Subventions
Organisme : NCI NIH HHS
ID : R01 CA181368
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA183976
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NIH HHS
ID : 1R01 CA183976
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA097190
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA237964
Pays : United States
Organisme : NIH HHS
ID : 1R01 CA181368
Pays : United States
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