神经纤维蛋白由 NF1 肿瘤抑制基因编码，是 RAS 通路的主要负调节因子，在各种癌症中经常发生突变。患有 I 型神经纤维瘤病 (NF1)（一种由种系 NF1 突变引起的肿瘤易感综合征）的女性患侵袭性乳腺癌的风险增加，且预后较差。 NF1 突变导致乳腺癌肿瘤发生的机制尚不清楚。因此，这项工作的目的是确定肿瘤形成前的基质改变，这些改变会导致 NF1 乳腺癌患者风险增加和预后较差。为了准确模拟 NF1 患者的种系单等位基因 NF1 突变，我们利用了 Nf1 缺陷的模型大鼠模型在出现高渗透性乳腺癌之前乳腺发育加速。我们发现，在肿瘤形成之前，Nf1 缺陷的大鼠乳腺中胶原蛋白含量增加，这与肿瘤发病年龄相关。此外，基因表达分析显示，大鼠乳腺中缺乏 Nf1 的成熟脂肪细胞胶原蛋白表达增加，并转变为成纤维细胞和前脂肪细胞表达谱。在体外分化中也观察到了谱系定型的这种变化，然而，流式细胞术分析并未显示乳腺脂肪源性间充质干细胞丰度的变化。总的来说，这项研究揭示了 Nf1 在乳腺胶原沉积和调节中先前未描述的作用脂肪细胞分化。除了揭示肿瘤形成机制之外，对癌前乳腺中脂肪细胞和胶原蛋白修饰的进一步研究将为制定 NF1 患者乳腺癌早期检测策略奠定基础。版权所有 © 2024 Arumugam、Tovar、Essenburg、Dischinger、Beddows、沃尔夫鲁姆、马达杰、特纳、芬斯特拉、加利克、科恩、尼科尔斯、谢里登、埃斯基贝尔、穆奈姆内、格拉维尔和斯廷斯玛。

Neurofibromin, coded by the NF1 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 NF1 mutation-have an increased risk of developing aggressive breast cancer with poorer prognosis. The mechanism by which NF1 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.To accurately model the germline monoallelic NF1 mutations in NF1 patients, we utilized an Nf1-deficient rat model with accelerated mammary development before presenting with highly penetrant breast cancer.We identified increased collagen content in Nf1-deficient rat mammary glands before tumor formation that correlated with age of tumor onset. Additionally, gene expression analysis revealed that Nf1-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 in vitro differentiation, however, flow cytometry analysis did not show a change in mammary adipose-derived mesenchymal stem cell abundance.Collectively, this study uncovered the previously undescribed role of Nf1 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.Copyright © 2024 Arumugam, Tovar, Essenburg, Dischinger, Beddows, Wolfrum, Madaj, Turner, Feenstra, Gallik, Cohen, Nichols, Sheridan, Esquibel, Mouneimne, Graveel and Steensma.