An AIB1 isoform alters enhancer access and enables progression of early-stage triple-negative breast cancer

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)4230-4241
Number of pages12
JournalCancer Research
Volume81
Issue number16
DOIs
StatePublished - Aug 15 2021

Bibliographical note

Funding Information:
G.M. Sharif reports grants from NIH and NCI during the conduct of the study. G.W. Pearson reports grants from NIH during the conduct of the study. S. Fineberg reports other support from AXDEV Corp. outside the submitted work. A. Wellstein reports grants from NIH during the conduct of the study. A.T. Riegel reports grants from NIH/NCI during the conduct of the study. No disclosures were reported by the other authors.

Funding Information:
The authors thank our Georgetown University colleagues Dr. Virginie Ory for contribution to the experiments as well as Drs. Eric Glasgow and Matthew R. Swift for their assistance in the zebrafish experiments. The project described used the Tissue Culture & Biobanking, Flow Cytometry & Cell Sorting, Microscopy & Imaging, Animal Model, Histopathology & Tissue, and Genomics & Epigenomics Shared Resources, which are partially supported by award number P30CA051008 (PI: L. Weiner) from the NCI. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or the NIH. Work was supported by NIH grants R01CA205632 (to A.T. Riegel, A. Wellstein, G.M. Sharif, M.H. Kushner, W.B. Kietzman), R01CA218670 (to G.W. Pearson, A. Nasir), and R21CA226542 (to A.T. Riegel, G.M. Sharif, M.H. Kushner, W.B. Kietzman). NCI T32 CA009686 (to G.T. Graham, M.H. Kushner, W.B. Kietzman), F31 CA232664 (to M.H. Kushner).

Publisher Copyright:
© 2021 American Association for Cancer Research

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