■神经纤维蛋白,由NF1肿瘤抑制基因编码,是RAS途径的主要负调节因子,在各种癌症中经常发生突变。患有I型神经纤维瘤病(NF1)的女性-由种系NF1突变引起的肿瘤易感性综合征-患侵袭性乳腺癌的风险增加,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间质改变,这些改变导致NF1乳腺癌患者的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,在出现高渗透性乳腺癌之前,我们使用了Nf1缺陷大鼠模型,该模型具有加速的乳腺发育。
■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,这与肿瘤发病年龄有关。此外,基因表达分析显示,大鼠乳腺中缺乏Nf1的成熟脂肪细胞的胶原蛋白表达增加,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谱系定型的这种改变,然而,流式细胞术分析未显示乳腺脂肪间充质干细胞丰度的变化.
■集体,这项研究揭示了以前未描述的Nf1在乳腺胶原沉积和调节脂肪细胞分化中的作用。除了揭示肿瘤形成的机制,进一步研究肿瘤前乳腺中的脂肪细胞和胶原修饰将为制定NF1患者乳腺癌的早期检测策略奠定基础.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.