Conditional knockout of N-Myc and STAT interactor disrupts normal mammary development and enhances metastatic ability of mammary tumors

Abstract

The process of organ development requires a delicate balance between cellular plasticity and differentiation. This balance is disrupted in cancer initiation and progression. N-Myc and STAT interactor (NMI: human or Nmi: murine) has emerged as a relevant player in the etiology of breast cancer. However, a fundamental understanding of its relevance to normal mammary biology is lacking. To gain insight into its normal function in mammary gland, we generated a mammary-specific Nmi knockout mouse model. We observed that Nmi protein expression is induced in mammary epithelium at the onset of pregnancy, in luminal cells and persists throughout lactation. Nmi knockout results in a precocious alveolar phenotype. These alveoli exhibit an extensive presence of nuclear β-catenin and enhanced Wnt/β-catenin signaling. The Nmi knockout pubertal ductal tree shows enhanced invasion of the mammary fatpad and increased terminal end bud numbers. Tumors from Nmi null mammary epithelium show a significant enrichment of poorly differentiated cells with elevated stem/progenitor markers, active Wnt/β-catenin signaling, highly invasive morphology as well as, increased number of distant metastases. Our study demonstrates that Nmi has a distinct role in the differentiation process of mammary luminal epithelial cell compartment and developmental aberrations resulting from Nmi absence contribute to metastasis and demonstrates that aberration in normal developmental program can lead to metastatic disease, highlighting the contribution and importance of luminal progenitor cells in driving metastatic disease.

Hypoxia re-programs 2′-O-Me modifications on ribosomal RNA

“…Hypoxia is one of the well-established drivers of epithelial-mesenchymal-transition (EMT). Multiple studies from our group have highlighted the importance of NMI (N-Myc and STAT interactor) protein in negatively impacting EMT ( Devine et al., 2014 ; Pruitt et al., 2018 ). NMI protein contains a previously uncharacterized RNA recognition motif (RRM) at aa.…”

“…Even though there is an absence of studies detailing effects of hypoxia on ribosome biogenesis, multiple studies have defined roles for hypoxia in regulating a program of epithelial-mesenchymal-plasticity ( Prakash et al., 2019 ; Williams et al., 2019 ). Studies from our lab have previously defined a critical role of NMI in tumor progression and metastasis via alterations in the EMT program ( Devine et al., 2014 ; Pruitt et al., 2018 ). Based on these studies, NMI presents as a critical regulator of epithelial-mesenchymal-plasticity.…”

NMI promotes cell proliferation through TGFβ/Smad pathway by upregulating STAT1 in colorectal cancer

“…However, NMI was demonstrated to act as a downstream target of N‐myc and to be negatively related to cell growth in neuroblastoma (Wang, Gao, Wang, Xia, & Liang, ). NMI also has been reported to suppress tumor invasion and metastasis by inhibiting NF‐κB pathways in gastric cancer (Hou et al, ); NMI inhibited the growth of breast cancer through upregulating the expression of Dkk1 (Fillmore et al, ); downregulation of NMI promoted lung adenocarcinoma growth, which was correlated with the upregulated expression of COX‐2 (Wang et al, ); Nmi loss enhanced the mammary carcinoma metastasis in model mice (Pruitt et al, ). However, its function in the progression of CRC is still unclear.…”

Disruption of STAT5A and NMI signaling axis leads to ISG20-driven metastatic mammary tumors

“…Our recent findings show that N-Myc and STAT interactor (NMI) is expressed in the mammary ductal epithelium at the onset of puberty and is induced in pregnancy and lactation. NMI expression is critical for ensuring the maintenance of differentiated luminal epithelial cells 8 . Our mammary-specific NMI knockout mouse revealed that NMI loss disrupts luminal differentiation in the mammary glands affecting alveologenesis and prompts the progression of tumors with aggressive metastatic characteristics 8 .…”

“…NMI expression is critical for ensuring the maintenance of differentiated luminal epithelial cells 8 . Our mammary-specific NMI knockout mouse revealed that NMI loss disrupts luminal differentiation in the mammary glands affecting alveologenesis and prompts the progression of tumors with aggressive metastatic characteristics 8 . In agreement with this, NMI protein expression is significantly decreased in 70% of patient specimens with metastatic breast cancer compared to primary tumors 8 , 9 .…”