An AIB1 Isoform Alters Enhancer Access and Enables Progression of Early-Stage Triple-Negative Breast Cancer.

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 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.

• Authors: Ghada M Sharif, Moray J Campbell, Apsra Nasir, Surojeet Sengupta, Garrett T Graham, Max H Kushner, William B Kietzman, Marcel O Schmidt, Gray W Pearson, Olivier Loudig, Susan Fineberg, Anton Wellstein, Anna T Riegel
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 16 Pg. 4230-4241 (08 15 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 34135000 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Protein Isoforms
• Receptors, Glucocorticoid
• Thiazolidinediones
• Dexamethasone
• NCOA3 protein, human
• Ncoa3 protein, mouse
• Nuclear Receptor Coactivator 3
• efatutazone

Topics

• 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, genetics)
• Phenotype
• Protein Isoforms
• RNA Splicing
• Receptors, Glucocorticoid (metabolism)
• Signal Transduction
• Thiazolidinediones (pharmacology)
• Triple Negative Breast Neoplasms (genetics, metabolism)
• Zebrafish