Nf1Deficiency Increases Mammary Collagen Deposition and Restricts Adipocyte Differentiation Before Tumor Formation

Abstract

ABSTRACTBACKGROUNDNeurofibromin, coded by theNF1tumor 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 germlineNF1mutation – have an increased risk of developing aggressive breast cancer with poorer prognosis. The mechanism by whichNF1mutations 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.METHODSTo accurately model the germline monoallelicNF1mutations in NF1 patients, we utilized anNf1-deficient rat model with accelerated mammary development before presenting with highly penetrant breast cancer.RESULTSWe identified increased collagen content inNf1-deficient rat mammary glands before tumor formation that correlated with age of tumor onset. Additionally, gene expression analysis revealed thatNf1-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 within vitrodifferentiation, however, flow cytometry analysis did not show a change in mammary adipose-derived mesenchymal stem cell abundance.CONCLUSIONCollectively, these studies uncovered the previously undescribed role ofNf1in 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.GRAPHICAL ABSTRACT