The Anti-Metastatic nm23-1 Gene Is Needed for the Final Step of Mammary Duct Maturation of the Mouse Nipple

Nm23/NDP kinases are multifunctional enzymes involved in the general homeostasis of triphosphate nucleosides. Numerous studies have shown that NDPKs also serve as regulatory factors of various cell activities, not always connected to nucleotide phosphorylation. In particular, the nme-1 gene, encoding the NM23-1/NDPKA protein, has been reported as a metastasis suppressor gene. This activity was validated in hepatocellular tumors induced in nm23-1 deficient mice. Yet, data describing the primary physiological functions of nm23-1/NDPKA is still scarce. We have characterized in depth the phenotype of nm23-1 deletion in the mammary gland in mice carrying whole body nm23-M1 invalidation. We also asked why the nm23-M1−/− mutant females displayed severe nursing disability. We found that the growth retardation of mutant virgin glands was due to reduced proliferation and apoptosis of the epithelial cells within the terminal end buds. The balance of pro/anti-apoptotic factors was impaired in comparison with wild type glands. In the lactating glands, the reduced proliferation rate persisted, but the apoptotic factors were unchanged. However, those defects did not seem to affect the gland maturation since the glands lacking nm23-1/NDPKA appeared morphologically normal. Thorough examination of all the functional aspects of the mammary glands revealed that lack of nm23-1/NDPKA does not impact the production or the ejection of milk in the lumen of lobuloalveolae. Interestingly, an epithelial plug was found to obstruct the extremity of the unique lactiferous duct delivering the milk out of the nipple. These cells, normally disappearing after lactation takes place, persisted in the mutant nipples. This work provides a rare instance of nm23-1/NDPKA physiological functions in the mammary glands and reveals its implication as a modulator factor of proliferation and apoptosis in this tissue.Nm23/NDP激酶（Nm23/NDP kinases）是一类参与三磷酸核苷整体稳态调控的多功能酶。多项研究表明，NDP激酶同时可作为多种细胞活动的调控因子，其功能并不局限于核苷酸磷酸化过程。具体而言，编码NM23-1/NDPKA蛋白的nme-1基因曾被报道为转移抑制基因，该功能已在nm23-1基因敲除小鼠诱导的肝细胞肿瘤中得到验证。然而，目前关于nm23-1/NDPKA核心生理功能的研究数据仍较为匮乏。本研究针对全身nm23-M1基因失活的小鼠，深入解析了乳腺组织中nm23-1基因敲除的表型特征，并探究了nm23-M1基因敲除纯合突变雌性小鼠出现严重泌乳障碍的原因。研究发现，突变体未生育小鼠的乳腺生长迟缓，源于末端芽上皮细胞的增殖能力下降与凋亡异常；与野生型小鼠乳腺相比，突变体中促/抗凋亡因子的平衡状态遭到破坏。在泌乳期乳腺中，上皮细胞增殖速率低下的情况持续存在，但凋亡因子的表达水平并未发生改变。尽管存在上述缺陷，nm23-1/NDPKA缺失的乳腺在形态学上仍表现正常，提示这些异常并未影响乳腺的成熟过程。对乳腺所有功能维度的全面检测显示，nm23-1/NDPKA的缺失并不会影响腺泡腔中乳汁的合成与排出。值得注意的是，研究团队在突变体小鼠中发现，一条负责将乳汁输送至乳头的特有泌乳导管末端被上皮栓阻塞；这类通常在泌乳结束后会发生消退的细胞，在突变体小鼠的乳头中持续存在。本研究首次较为系统地阐明了nm23-1/NDPKA在乳腺组织中的生理功能，并揭示其作为该组织中增殖与凋亡过程的调控因子发挥作用。