Abstract
Molecular dynamics of developmental processes are repurposed by cancer cells to support cancer initiation and progression. Disruption of the delicate balance between cellular differentiation and plasticity during mammary development leads to breast cancer initiation and metastatic progression. STAT5A is essential for differentiation of secretory mammary alveolar epithelium. Active STAT5A characterizes breast cancer patients for favorable prognosis. N-Myc and STAT Interactor protein (NMI) was initially discovered as a protein that interacts with various STATs; however, the relevance of these interactions to normal mammary development and cancer was not known. We observe that NMI protein is expressed in the mammary ductal epithelium at the onset of puberty and is induced in pregnancy. NMI protein is decreased in 70% of patient specimens with metastatic breast cancer compared to primary tumors. Here we present our finding that NMI and STAT5A cooperatively mediate normal mammary development. Loss of NMI in vivo caused a decrease in STAT5A activity in normal mammary epithelial as well as breast cancer cells. Analysis of STAT5A mammary specific controlled genetic program in the context of NMI knockout revealed ISG20 (interferon stimulated exonuclease gene 20, a protein involved in rRNA biogenesis) as an unfailing negatively regulated target. Role of ISG20 has never been described in metastatic process of mammary tumors. We observed that overexpression of ISG20 is increased in metastases compared to matched primary breast tumor tissues. Our observations reveal that NMI-STAT5A mediated signaling keeps a check on ISG20 expression via miR-17–92 cluster. We show that uncontrolled ISG20 expression drives tumor progression and metastasis.
Highlights
Distorted manifestation of developmental processes, such as cellular plasticity, are used by cancer cells to support cancer initiation and progression to metastatic disease[1,2]
Development of mammary luminal progenitor cells is controlled by the transcription factor STAT5A14
We examined the expression of NMyc and signal transducer and activator of transcription (STAT) Interactor protein (NMI) and STAT5A in single-cell RNA sequencing of the luminal differentiation trajectory of mouse mammary epithelial cells (MECs)[15]
Summary
Distorted manifestation of developmental processes, such as cellular plasticity, are used by cancer cells to support cancer initiation and progression to metastatic disease[1,2]. NMI expression coincides with active STAT5A in HC11 mammary cell differentiation Our findings revealed concurrent increase in NMI and active STAT5A during mammary differentiation and prompted us to investigate if there is a common signaling network governed by these proteins.
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