AUTHOR=Arumugam Menusha , Tovar Elizabeth A. , Essenburg Curt J. , Dischinger Patrick S. , Beddows Ian , Wolfrum Emily , Madaj Zach B. , Turner Lisa , Feenstra Kristin , Gallik Kristin L. , Cohen Lorna , Nichols Madison , Sheridan Rachel T. C. , Esquibel Corinne R. , Mouneimne Ghassan , Graveel Carrie R. , Steensma Matthew R. 

TITLE=Nf1 deficiency modulates the stromal environment in the pretumorigenic rat mammary gland

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=12

YEAR=2024

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2024.1375441

DOI=10.3389/fcell.2024.1375441

ISSN=2296-634X

ABSTRACT=<sec><title>Background:</title><p>Neurofibromin, coded by the <italic>NF1</italic> tumor suppressor gene, is the main negative regulator of the RAS pathway and is frequently mutated in various cancers. Women with Neurofibromatosis Type I (NF1)–a tumor predisposition syndrome caused by a germline <italic>NF1</italic> mutation–have an increased risk of developing aggressive breast cancer with poorer prognosis. The mechanism by which <italic>NF1</italic> mutations lead to breast cancer tumorigenesis is not well understood. Therefore, the objective of this work was to identify stromal alterations before tumor formation that result in the increased risk and poorer outcome seen among NF1 patients with breast cancer.</p></sec><sec><title>Approach:</title><p>To accurately model the germline monoallelic <italic>NF1</italic> mutations in NF1 patients, we utilized an <italic>Nf1-</italic>deficient rat model with accelerated mammary development before presenting with highly penetrant breast cancer.</p></sec><sec><title>Results:</title><p>We identified increased collagen content in <italic>Nf1</italic>-deficient rat mammary glands before tumor formation that correlated with age of tumor onset. Additionally, gene expression analysis revealed that <italic>Nf1</italic>-deficient mature adipocytes in the rat mammary gland have increased collagen expression and shifted to a fibroblast and preadipocyte expression profile. This alteration in lineage commitment was also observed with <italic>in vitro</italic> differentiation, however, flow cytometry analysis did not show a change in mammary adipose-derived mesenchymal stem cell abundance.</p></sec><sec><title>Conclusion:</title><p>Collectively, this study uncovered the previously undescribed role of <italic>Nf1</italic> in mammary collagen deposition and regulating adipocyte differentiation. In addition to unraveling the mechanism of tumor formation, further investigation of adipocytes and collagen modifications in preneoplastic mammary glands will create a foundation for developing early detection strategies of breast cancer among NF1 patients.</p></sec>