Loss of rhomboid protease RHBDL4 delays tumour initiation in a mouse model of breast cancer

Despite advances in detection and treatment, breast cancer still claims more than 600,000 lives each year. Understanding the molecular pathways that initiate and sustain tumour growth is essential for improving patient outcomes. Among the regulators of these pathways are intramembrane proteases such RHBDL4, an intramembrane rhomboid serine protease. RHBDL4 has been implicated in several cancers, including breast cancer, yet its precise role in tumour progression remains unclear. Using the MMTV-PyMT mouse model to investigate RHBDL4's contribution to mammary tumourigenesis; we found that its genetic loss markedly delayed tumour onset, impeded early tumour growth, and suppressed AKT1 signalling and associated metabolic gene programs. Immunohistochemical analyses found RHBDL4 knockout mammary ducts exhibited reduced proliferative signalling and increased apoptotic signalling. In contrast, RHBDL4 loss had no detectable effect on metastasis or late-stage tumour progression, indicating that RHBDL4 functions primarily during the early phases of tumour development. These findings identify RHBDL4 as a regulator of early oncogenic transformation and reveal its temporally restricted role in mammary tumourigenesis. Overall design: RNAseq profiling of wild-type and RHBDL4-knockout mouse tumours at 5 weeks post tumour onset.