Depletion of the Transcriptional Coactivator Amplified in Breast Cancer 1 (AIB1) Uncovers Functionally Distinct Subpopulations in Triple-Negative Breast Cancer

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2019-10, Vol.21 (10), p.963-973
• Main Authors: Saenz, FR, Ory, V, Schmidt, MO, Kallakury, BV, Mueller, SC, Furth, PA, Wellstein, A, Riegel, AT
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Clonal Evolution - genetics; Disease Models, Animal; Exome Sequencing; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Mice; Nuclear Receptor Coactivator 3 - metabolism; Original article; Phenotype; RNA, Small Interfering - genetics; Signal Transduction; Transcriptome; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - mortality; Triple Negative Breast Neoplasms - pathology
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2019.07.001

The transcriptional coactivator Amplified in Breast Cancer 1 (AIB1) plays a major role in the progression of hormone and HER2-dependent breast cancers but its role in triple negative breast cancer (TNBC) is undefined. Here, we report that established TNBC cell lines, as well as cells from a TNBC patient-derived xenograft (PDX) that survive chemotherapy treatment in vitro express lower levels of AIB1 protein. The surviving cell population has an impaired tube-formation phenotype when cultured onto basement membrane, a property shared with TNBC cells that survive shRNA-mediated depletion of AIB1 (AIB1LOW cells). DNA analysis by exome sequencing revealed that AIB1LOW cells represent a distinct subpopulation. Consistent with their in vitro phenotype AIB1LOW cells implanted orthotopically generated slower growing tumors with less capacity for pulmonary metastases. Gene expression analysis of cultured cells and tumors revealed that AIB1LOW cells display a distinct expression signature of genes in pro-inflammatory pathways, cell adhesion, proteolysis and tissue remodeling. Interestingly, the presence of this AIB1LOW expression signature in breast cancer specimens is associated with shorter disease free survival of chemotherapy treated patients. We concluded that TNBC cell lines contain heterogeneous populations with differential dependence on AIB1 and that the gene expression pattern of AIB1LOW cells may represent a signature indicative of poor response to chemotherapy in TNBC patients.