IGFBP3 Promotes Mammary Stem Cells Activity and Tumorigenesis by Regulating IGF Bioavailability

Mammary stem cells (MaSCs) play important roles in mammary gland homeostasis. A better understanding of MaSC activity enhances our knowledge of breast cancer initiation and progression, particularly in the context of triple-negative breast cancer (TNBC). Until now, the molecular mechanisms of MaSCs have remained elusive. Our current research has unveiled a significant enrichment of IGFBP3 expression in normal MaSCs, highlighting its indispensable role in maintaining MaSCs stemness and mammary gland development. Moreover, we show that IGFBP3 promotes breast cancer tumorigenesis and progression. Mechanistically, IGFBP3 regulates IGF1/2 bioavailability under the action of MMPs (such as MMP3), activating the IGF1R receptor and its downstream AKT and ERK1/2 signaling pathways. In clinical samples, high expression of either IGFBP3 or MMP3 is associated with poor prognosis in ER-negative or TNBC patients. Future studies should investigate the potential therapeutic benefit of IGFBP3 in TNBC. Overall design: RNA-seq profiling of mammary stem cells and luminal cells. RNA-seq profiling of SCP28 cells with IGFBP3 KD or not.