Mycn Is Essential for Pubertal Mammary Gland Development and Promotes the Activation of Bcl11b-Maintained Quiescent Stem Cells

This investigation examines the function of the mouse <i>Mycn</i> gene in regulating and activating quiescent mammary stem cells, which are vital for mammary gland development. The mammary gland, consisting of luminal and basal cells, progresses through complex developmental stages from embryonic development through puberty, adulthood, pregnancy, lactation, and involution. Quiescent stem cells, existing in a reversible non-proliferative state, are essential for gland maintenance, yet their activation mechanisms remain poorly understood. Mycn, a member of the Myc/MYC oncogene family, is recognized for its roles in embryonic development and cancer, notably aggressive neuroblastoma and triple-negative breast cancer. Through single-cell RNA sequencing (scRNA-seq), CRISPR knockout, and overexpression experiments, this study demonstrates that Mycn is highly enriched in the terminal end buds (TEBs) of the pubertal mammary gland, particularly in basal cells, and is critical for ductal development. Both deletion and overexpression of <i>Mycn</i> diminish the stemness and regenerative capacity of mammary stem cells. Mycn enhances cell proliferation while downregulating quiescent stem cell markers and regulators, including Bcl11b and Tspan8, affecting stem cell maintenance and differentiation. This research clarifies the regulatory role of Bcl11b in controlling Tspan8 expression and demonstrates that Mycn indirectly targets both under normal conditions. Maintaining appropriate levels of Mycn expression is essential for normal development and cancer prevention. These insights contribute to understanding diseases and aggressive cancers, including triple-negative breast cancer (TNBC), and suggest potential therapeutic approaches.