An AIB1 Isoform Alters Enhancer Access and Enables Progression of Early-Stage Triple-Negative Breast Cancer
©2021 American Association for Cancer Research..
AIB1Δ4 is an N-terminally truncated isoform of the oncogene amplified in breast cancer 1 (AIB1) with increased expression in high-grade human ductal carcinoma in situ (DCIS). However, the role of AIB1Δ4 in DCIS malignant progression has not been defined. Here we CRISPR-engineered RNA splice junctions to produce normal and early-stage DCIS breast epithelial cells that expressed only AIB1Δ4. These cells showed enhanced motility and invasion in 3D cell culture. In zebrafish, AIB1Δ4-expressing cells enabled invasion of parental cells when present in a mixed population. In mouse xenografts, a subpopulation of AIB1Δ4 cells mixed with parental cells enhanced tumor growth, recurrence, and lung metastasis. AIB1Δ4 chromatin immunoprecipitation sequencing revealed enhanced binding to regions including peroxisome proliferator-activated receptor (PPAR) and glucocorticoid receptor (GR) genomic recognition sites. H3K27ac and H3K4me1 genomic engagement patterns revealed selective activation of breast cancer-specific enhancer sites by AIB1Δ4. AIB1Δ4 cells displayed upregulated inflammatory response genes and downregulated PPAR signaling gene expression patterns. In the presence of AIB1Δ4 enabler cells, parental cells increased NF-κB and WNT signaling. Cellular cross-talk was inhibited by the PPARγ agonist efatutazone but was enhanced by treatment with the GR agonist dexamethasone. In conclusion, expression of the AIB1Δ4-selective cistrome in a small subpopulation of cells triggers an "enabler" phenotype hallmarked by an invasive transcriptional program and collective malignant progression in a heterogeneous tumor population. SIGNIFICANCE: A minor subset of early-stage breast cancer cells expressing AIB1Δ4 enables bulk tumor cells to become invasive, suggesting that selective eradication of this population could impair breast cancer metastasis.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:81 |
|---|---|
| Enthalten in: |
Cancer research - 81(2021), 16 vom: 15. Aug., Seite 4230-4241 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Sharif, Ghada M [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 07.01.2022 Date Revised 16.02.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1158/0008-5472.CAN-20-3625 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM326825975 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM326825975 | ||
| 003 | DE-627 | ||
| 005 | 20231225195432.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1158/0008-5472.CAN-20-3625 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1089.xml |
| 035 | |a (DE-627)NLM326825975 | ||
| 035 | |a (NLM)34135000 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Sharif, Ghada M |e verfasserin |4 aut | |
| 245 | 1 | 3 | |a An AIB1 Isoform Alters Enhancer Access and Enables Progression of Early-Stage Triple-Negative Breast Cancer |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 07.01.2022 | ||
| 500 | |a Date Revised 16.02.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2021 American Association for Cancer Research. | ||
| 520 | |a AIB1Δ4 is an N-terminally truncated isoform of the oncogene amplified in breast cancer 1 (AIB1) with increased expression in high-grade human ductal carcinoma in situ (DCIS). However, the role of AIB1Δ4 in DCIS malignant progression has not been defined. Here we CRISPR-engineered RNA splice junctions to produce normal and early-stage DCIS breast epithelial cells that expressed only AIB1Δ4. These cells showed enhanced motility and invasion in 3D cell culture. In zebrafish, AIB1Δ4-expressing cells enabled invasion of parental cells when present in a mixed population. In mouse xenografts, a subpopulation of AIB1Δ4 cells mixed with parental cells enhanced tumor growth, recurrence, and lung metastasis. AIB1Δ4 chromatin immunoprecipitation sequencing revealed enhanced binding to regions including peroxisome proliferator-activated receptor (PPAR) and glucocorticoid receptor (GR) genomic recognition sites. H3K27ac and H3K4me1 genomic engagement patterns revealed selective activation of breast cancer-specific enhancer sites by AIB1Δ4. AIB1Δ4 cells displayed upregulated inflammatory response genes and downregulated PPAR signaling gene expression patterns. In the presence of AIB1Δ4 enabler cells, parental cells increased NF-κB and WNT signaling. Cellular cross-talk was inhibited by the PPARγ agonist efatutazone but was enhanced by treatment with the GR agonist dexamethasone. In conclusion, expression of the AIB1Δ4-selective cistrome in a small subpopulation of cells triggers an "enabler" phenotype hallmarked by an invasive transcriptional program and collective malignant progression in a heterogeneous tumor population. SIGNIFICANCE: A minor subset of early-stage breast cancer cells expressing AIB1Δ4 enables bulk tumor cells to become invasive, suggesting that selective eradication of this population could impair breast cancer metastasis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 7 | |a Protein Isoforms |2 NLM | |
| 650 | 7 | |a Receptors, Glucocorticoid |2 NLM | |
| 650 | 7 | |a Thiazolidinediones |2 NLM | |
| 650 | 7 | |a Dexamethasone |2 NLM | |
| 650 | 7 | |a 7S5I7G3JQL |2 NLM | |
| 650 | 7 | |a NCOA3 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.3.1.48 |2 NLM | |
| 650 | 7 | |a Ncoa3 protein, mouse |2 NLM | |
| 650 | 7 | |a EC 2.3.1.48 |2 NLM | |
| 650 | 7 | |a Nuclear Receptor Coactivator 3 |2 NLM | |
| 650 | 7 | |a EC 2.3.1.48 |2 NLM | |
| 650 | 7 | |a efatutazone |2 NLM | |
| 650 | 7 | |a M17ILL71MC |2 NLM | |
| 700 | 1 | |a Campbell, Moray J |e verfasserin |4 aut | |
| 700 | 1 | |a Nasir, Apsra |e verfasserin |4 aut | |
| 700 | 1 | |a Sengupta, Surojeet |e verfasserin |4 aut | |
| 700 | 1 | |a Graham, Garrett T |e verfasserin |4 aut | |
| 700 | 1 | |a Kushner, Max H |e verfasserin |4 aut | |
| 700 | 1 | |a Kietzman, William B |e verfasserin |4 aut | |
| 700 | 1 | |a Schmidt, Marcel O |e verfasserin |4 aut | |
| 700 | 1 | |a Pearson, Gray W |e verfasserin |4 aut | |
| 700 | 1 | |a Loudig, Olivier |e verfasserin |4 aut | |
| 700 | 1 | |a Fineberg, Susan |e verfasserin |4 aut | |
| 700 | 1 | |a Wellstein, Anton |e verfasserin |4 aut | |
| 700 | 1 | |a Riegel, Anna T |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cancer research |d 1945 |g 81(2021), 16 vom: 15. Aug., Seite 4230-4241 |w (DE-627)NLM000001740 |x 1538-7445 |7 nnns |
| 773 | 1 | 8 | |g volume:81 |g year:2021 |g number:16 |g day:15 |g month:08 |g pages:4230-4241 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1158/0008-5472.CAN-20-3625 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 81 |j 2021 |e 16 |b 15 |c 08 |h 4230-4241 | ||