Nucling, a Novel Apoptosis-associated Protein, Controls Mammary Gland Involution by Regulating NF-κB and STAT3

Postpartum mammary gland involution is the physiological process by which the lactating gland returns to its pre-pregnant state. In rodent models, the microenvironment of mammary gland involution is sufficient to induce enhanced tumor cell growth, local invasion, and metastasis. Therefore, a deeper understanding of the physiological regulation of involution may provide in-depth information on breast cancer therapy. We herein identified Nucling as an important regulator of involution of the mammary gland. A knock-out mouse model was generated and revealed that postpartum involution were impaired in mice lacking Nucling. Involution is normally associated with an increase in the activation of NF-κB and STAT3, which is required for the organized regulation of involution, and was observed in WT glands, but not in the absence of Nucling. Furthermore, the loss of Nucling led to the suppression of Calpain-1, IL-6, and C/EBPδ factors, which are known to be essential for normal involution. The number of M2 macrophages, which are crucial for epithelial cell death and adipocyte repopulation after weaning, was also reduced in Nucling-KO glands. Taken together, the results of the present study demonstrated that Nucling played an important role in mammary gland involution by regulating NF-κB and STAT3 signaling pathways. Background: Nucling is identified as a novel regulator of apoptosis, but its roles in mammary gland remains unknown. Results: Loss of Nucling led to an inhibited apoptosis and impaired mammary gland involution. Conclusion: Nucling controlled NF-κB and STAT3 activities to mediate involution. Significance: Elucidation of the physiological role of Nucling in this process may provide useful insight into breast cancer therapy.