Functions of the C/EBPβ isoforms in breast cancer

Breast cancer is the most commonly diagnosed type of cancer in women and the survival outcome is strongly dependent on the stage of breast cancer at diagnosis. Therefore, it is essential to identify oncogenic factors that contribute to breast cancer development and metastasis. The transcription factor C/EBPβ is known to regulate cell proliferation and differentiation in a variety of tissues. The transactivation capacity of C/EBPβ is largely determined by the ratio between the isoforms C/EBPβ-LAP and C/EBPβ-LIP. Previous studies have shown that C/EBPβ-LIP-depleted mice display improved metabolic health, a prolonged lifespan, and reduced cancer incidence. Other studies have found high expression of LIP in grade III, Estrogen receptor (ER) and Progesterone (PR) receptor negative human breast cancer and have linked high LIP expression with increased mammary epithelial proliferation. We find that cell lines derived from triple-negative breast cancer (TNBC, lacking the Estrogen and Progesterone receptors and HER2 expression) have a very high LIP/LAP ratio. Reducing the LIP/LAP ratio by exogenous expression of LAP in TNBC cell lines reduces migration and invasion of the breast cancer cells. Moreover, the overexpression of LIP promotes cell migration of untransformed mammary epithelial cells. Transcriptomics data obtained from TNBC cells with CEBPB knockout show a regulation of migration and extracellular matrix-related genes. Our data propose a role for the LIP/LAP ratio in the regulation of breast cancer cell migration and ECM remodelling, two key characteristics that are associated with the aggressive phenotype of TNBC cells.