The process of development requires a delicate balance between plasticity and differentiation. This balance is disrupted in cancer initiation and progression, ultimately ending in metastasis and plummeting rates of patient survival. Recent findings from our lab have revealed that protein expression of evolutionarily conserved, N-Myc and STAT Interactor (NMI) is decreased in 70% of primary patient specimens with metastatic breast cancer. To study how Nmi loss facilitates metastatic behavior and gain insight into its role in normal mammary biology, we created a novel mammary specific Nmi knock out mouse model, which we then challenged with carcinogen and oncogene induced tumorigenesis. Our studies show that Nmi is induced at the onset of pregnancy and its expression remains throughout lactation. Furthermore, prolactin stimulation and differentiation of HC11 murine mammary epithelial cells is accompanied by up-regulation of Nmi. STAT5 is the downstream effector of prolactin and is essential for differentiation of secretory alveolar epithelium. NMI interacts with STAT5 and this interaction appears to be critical to normal differentiation of mammary epithelium. Indeed, loss of Nmi in vivo caused a decrease in STAT5 activity and a subsequent transcriptomic shift in mammary epithelial and breast cancer cells. Moreover, knockdown of Nmi in HC11 cells impedes the expression of beta-casein upon differentiation with prolactin. Concurrently, Nmi knock out alveoli exhibit an extensive presence of nuclear beta-catenin, a mediator of stem cell maintenance in the mammary gland. As a result, mice exhibit an increased number of alveoli and more proliferating mammary epithelial cells (MECs). The Nmi knock out pubertal ductal tree extends into the mammary fat pad at an accelerated rate and exhibits enhanced terminal end bud numbers, a phenotype that mirrors mice altered for Wnt signaling. Tumors derived from Nmi null mammary epithelium contain significantly more cells with stem and progenitor markers, indicating that these tumors are less differentiated than their littermate counterparts. In addition, Nmi null mammary tumors exhibit invasive morphology as well as enhanced distant metastasis. We observe that conditional Nmi loss disrupts differentiation in the mammary gland and promotes the progression of tumors with aggressive metastatic characteristics.
Citation Format: Hawley Christine Pruitt, Brandon J. Metge, Shannon E. Weeks, Dongquan Chen, Shi Wei, Lalita A. Shevde, Rajeev S. Samant. Conditional knockout of N-Myc and STAT Interactor disrupts normal mammary development and enhances metastatic ability of mammary tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1046. doi:10.1158/1538-7445.AM2017-1046