Nf1 deficiency accelerates mammary development and promotes luminal-basal plasticity

Tovar, E. A.; Arumugam, M.; Essenburg, C. J.; Dischinger, P. S.; Grit, J. L.; Callaghan, M.; Sheridan, R. T. C.; Turner, L.; Esquibel, C. R.; Feenstra, K.; Madaj, Z.; Beddows, I.; Graveel, C. R.; Steensma, M. R.

doi:10.1101/2022.12.22.520633

bioRxiv · 10.1101/2022.12.22.520633

Nf1 deficiency accelerates mammary development and promotes luminal-basal plasticity

Tovar, E. A.·Arumugam, M.·Essenburg, C. J.·Dischinger, P. S.·Grit, J. L.·Callaghan, M.·Sheridan, R. T. C.·Turner, L.·Esquibel, C. R.·Feenstra, K.·Madaj, Z.·Beddows, I.·Graveel, C. R.·Steensma, M. R.

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Abstract

The tumor suppressor NF1 is a critical driver of sporadic breast cancer and NF-related breast cancers. We utilized distinct Nf1-deficient immunocompetent rat models to investigate Nf1 function in mammary development and homeostasis. Here we demonstrate that Nf1 deficiency dramatically accelerates mammary morphogenesis, alters TEB cell organization, and proliferation. Notably, we observed a shift in luminal-basal epithelial lineage commitment within Nf1-deficient lines with early tumor onset. In addition, we detected subpopulations of hybrid EMT cells (Ecad+/CK14+) within the invasive edge and stroma of Nf1-deficient tumors. Nf1 deficiency restricted luminal progenitor potential and resulted in gene expression changes associated with decreased cell adhesion and increased EMT signatures. Together our findings support a model in which Nf1 loss of function results in lineage plasticity throughout mammary morphogenesis and promotes EMT-mediated invasion. This study reveals a previously unknown role for the tumor suppressor neurofibromin in mammary homeostasis and phenotypic plasticity during breast cancer progression.

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Tovar, E. A., Arumugam, M., Essenburg, C. J., Dischinger, P. S., Grit, J. L., Callaghan, M., Sheridan, R. T. C., Turner, L., Esquibel, C. R., Feenstra, K., Madaj, Z., Beddows, I., Graveel, C. R., Steensma, M. R.. 2022-12-22. Nf1 deficiency accelerates mammary development and promotes luminal-basal plasticity. https://doi.org/10.1101/2022.12.22.520633

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