An integrated network analysis for unveiling crucial transcription factors in triple negative breast cancer

Among breast cancer subtypes, triple-negative breast cancer (TNBC) is the most aggressive with the highest rates of metastatic disease. TNBC is characterized by the lack expression of estrogen receptor, progesterone receptor, and epidermal growth factor receptor 2, and, consequently, it does not respond to the standard hormonal therapy. Thus, the development of new targeted therapies for TNBC is urgently needed. To address this issue, here we applied SWIM - a software able to unveil a small pool of genes (called switch genes) associated with drastic changes in cell phenotypes - to gene expression profiles of triple-negative breast invasive carcinoma and matched-normal tissues downloaded from The Cancer Genome Atlas. SWIM unveiled 293 switch genes, including the transcription factor HMGA1 whose high expression has been recently associated with breast cancer aggressiveness and metastasis. The oncogenic properties of HMGA1 are mainly due to its capacity to form complexes with other transcription factors that regulate the expression of genes involved in tumor progression and metastasis. In order to identify new putative transcription factors that could cooperate with HMGA1, we focused on the 12 switch genes that correlated positively with HMGA1 and showed a transcription factor activity. The activation of HMGA1 and these other 12 TF switch genes could have a key role in the transition from the physiological to pathological state of TNBC subtype.