PUBLICATION
An AIB1 isoform alters enhancer access and enables progression of early stage triple-negative breast cancer
- Authors
- Sharif, G.M., Campbell, M.J., Nasir, A., Sengupta, S., Graham, G.T., Kushner, M.H., Kietzman, W.B., Schmidt, M.O., Pearson, G.W., Loudig, O., Fineberg, S., Wellstein, A., Riegel, A.T.
- ID
- ZDB-PUB-210622-3
- Date
- 2021
- Source
- Cancer research 81(16): 4230-4241 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- CRISPR-Cas Systems
- Cell Culture Techniques, Three Dimensional
- Cell Line, Tumor
- Dexamethasone/chemistry
- Disease Progression
- Electric Impedance
- Enhancer Elements, Genetic
- Female
- Humans
- Lung Neoplasms/pathology
- Mice
- Mice, SCID
- Neoplasm Invasiveness
- Neoplasm Metastasis
- Neoplasm Transplantation
- Nuclear Receptor Coactivator 3/chemistry
- Nuclear Receptor Coactivator 3/genetics*
- Phenotype
- Protein Isoforms
- RNA Splicing
- Receptors, Glucocorticoid/metabolism
- Signal Transduction
- Thiazolidinediones/pharmacology
- Triple Negative Breast Neoplasms/genetics*
- Triple Negative Breast Neoplasms/metabolism*
- Zebrafish
- PubMed
- 34135000 Full text @ Cancer Res.
Citation
Sharif, G.M., Campbell, M.J., Nasir, A., Sengupta, S., Graham, G.T., Kushner, M.H., Kietzman, W.B., Schmidt, M.O., Pearson, G.W., Loudig, O., Fineberg, S., Wellstein, A., Riegel, A.T. (2021) An AIB1 isoform alters enhancer access and enables progression of early stage triple-negative breast cancer. Cancer research. 81(16):4230-4241.
Abstract
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 ChIP-seq 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 NFκB and WNT signaling. Cellular crosstalk 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping