Mechanisms that impact metastatic progression of triple negative breast cancer

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There is a notably high incidence of breast cancer among younger military women (20% to 40% higher). The incident rate of breast cancer for active duty women is seven times higher than the average incident rate of fifteen other cancer types across all service members. An estimated 90% of deaths due to breast cancer are a consequence of metastatic disease. Thus, metastasis is a formidable and clearly an unmet challenge. We identified that NMI (N-Myc Interactor) protein is undetectable in more than 60% of primary breast tumors that had undergone metastatic dissemination. To recapitulate this clinical scenario, we generated a mammary specific-NMI knockout (Nmi-KO) mouse. In this model, we deciphered that loss of NMI allows for unrestrained signaling through the Wnt/β-catenin pathway and enables mesenchymal transition (EMT) of mammary tumors cells leading to increased metastasis. We found that NMI protein loss is observed predominantly in triple negative breast cancers (TNBC). TNBC is inherently highly invasive and metastatic and is recognized for aberrantly activated Wnt/β-catenin signaling. While investigating cellular adaptations of TNBC to low doses of a Wnt/β-catenin inhibitor, iCRT14, we observed that iCRT14 clearly decreased the number of nucleoli per TNBC cell. The nucleolus is the primary site of ribosomal RNAs (rRNA) synthesis and assembly with ribosomal proteins. It is a vital component in the ability of a cancer cell to meet the dynamic metabolic demands of tumor progression. Classical pathologic diagnosis of tumor tissue has revealed that nucleolar hypertrophy and increased nucleolar number are predictive and prognostic parameters of increased mortality. Our observations reveal that TNBCs show increased number of nucleoli per cell compared to non-TNBC specimens. Despite the importance of Wnt/β-catenin signaling, there is a clear gap in knowledge about the relevance of this pathway to nucleolar functions, specifically in TNBCs. We hypothesize that TNBCs are `addicted to' elevated ribosome biogenesis. Our proposed investigations are designed to test if inhibition of Wnt/β-catenin signaling will be an effective approach to disable ribosome biogenesis of TNBCs, specifically in those that lack NMI expression. While Wnt/β-catenin signaling has been one of the major factors driving TNBC metastases, therapeutic strategies are still evolving. Our research efforts will advance this field and unravel critical information that identifies the novel drug targets. Overall our efforts are congruent with the mission of the VA women's health initiative.