Sumoylation Pathway Is Required to Maintain the Basal Breast Cancer Subtype

• Published in: Cancer cell 2014-06, Vol.25 (6), p.748-761
• Main Authors: Bogachek, Maria V., Chen, Yizhen, Kulak, Mikhail V., Woodfield, George W., Cyr, Anthony R., Park, Jung M., Spanheimer, Philip M., Li, Yingyue, Li, Tiandao, Weigel, Ronald J.
• Format: Article
• Language: English
• Subjects: Animals; Breast Neoplasms - classification; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cell Line, Tumor; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Mice; Mice, Nude; Multigene Family; Neoplasms, Basal Cell - classification; Neoplasms, Basal Cell - drug therapy; Neoplasms, Basal Cell - genetics; Neoplasms, Basal Cell - metabolism; Small Ubiquitin-Related Modifier Proteins - genetics; Small Ubiquitin-Related Modifier Proteins - metabolism; Sumoylation - drug effects; Sumoylation - genetics; Transcription Factor AP-2 - genetics; Transcription Factor AP-2 - metabolism; Transcriptional Activation; Transfection; Treatment Outcome; Xenograft Model Antitumor Assays
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2014.04.008

The TFAP2C/AP-2γ transcription factor regulates luminal breast cancer genes, and loss of TFAP2C induces epithelial-mesenchymal transition. By contrast, the highly homologous family member, TFAP2A, lacks transcriptional activity at luminal gene promoters. A detailed structure-function analysis identified that sumoylation of TFAP2A blocks its ability to induce the expression of luminal genes. Disruption of the sumoylation pathway by knockdown of sumoylation enzymes, mutation of the SUMO-target lysine of TFAP2A, or treatment with sumoylation inhibitors induced a basal-to-luminal transition, which was dependent on TFAP2A. Sumoylation inhibitors cleared the CD44+/hi/CD24−/low cell population characterizing basal cancers and inhibited tumor outgrowth of basal cancer xenografts. These findings establish a critical role for sumoylation in regulating the transcriptional mechanisms that maintain the basal cancer phenotype. [Display omitted] •Maintenance of the luminal or basal breast cancer phenotype is a dynamic process•TFAP2C has a unique role in maintaining the luminal breast cancer phenotype•SUMO inhibition causes TFAP2A to acquire ability to regulate luminal genes•SUMO inhibition clears the CD44+/hi/CD24−/low population in basal breast cancers Bogachek et al. show that TFAP2A is a sumoylation target and that inhibiting its SUMO conjugation disrupts the transcriptional mechanisms maintaining the basal breast cancer phenotype diminishes the CD44+/hi/CD24−/low population in basal breast cancer lines and reduces their xenograft formation.