TRPS1 maintains luminal progenitors in the mammary gland by repressing SRF/MRTF activity

Abstract The transcription factor TRPS1 is a context-dependent oncogene in breast cancer [1] [2] [3] [4] [5]. In the mammary gland, TRPS1 activity is restricted to the luminal population and is critical during puberty and pregnancy [2]. Its function in the resting state remains however unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy adult mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. We show that TRPS1 activity is essential to maintain a functional luminal progenitor compartment. This requires the repression of both YAP/TAZ and SRF/MRTF activities, TRPS1 represses SRF/MRTF activity indirectly by modulating RhoA activity. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors intrinsically linked to mechanotransduction in the mammary gland. It also provides new insights into the oncogenic functions of TRPS1 as luminal progenitors are likely the cells of origin of many breast cancers. Significance statement The transcription factor TRPS1 is a context-dependent oncogene in breast cancer. It is unclear how TRPS1 contributes to cancer development and whether it could be a target for therapy. Here we established a mouse model mimicking the systemic effect of TRPS1 drug targeting. With this model, we can show that TRPS1 depletion does not impact the fitness of the animals and that the role of TRPS1 is to maintain a functional luminal progenitor pool in the mammary gland. Mechanistically, TRPS1 represses a mechano-transduction program preventing their commitment to an alveolar fate. Because there is growing evidence that breast cancer originates from the expansion of altered luminal progenitors, our work provides valuable insights into the understanding of breast cancer initiation.