Transcriptome analysis reveals differences in cell cycle, growth and migration related genes that distinguish fibroblasts derived from pre-invasive and invasive breast cancer.
Transcriptome analysis reveals differences in cell cycle, growth and migration related genes that distinguish fibroblasts derived from pre-invasive and invasive breast cancer.
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DOI：
10.3389/fonc.2023.1130911
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发表时间：
2023
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
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作为侵袭前乳腺癌最常见的形式，导管原位癌（DCIS）在美国每年影响超过50,000名女性。尽管标准化治疗包括乳房肿瘤切除术和放射治疗，高达25%的DCIS患者经历疾病复发，通常伴有浸润性导管癌（IDC），这表明一部分患者可能治疗不足。由于大多数DCIS病例不会发展为侵袭，许多患者可能会经历过度治疗。通过了解DCIS与IDC进展相关的潜在过程，我们可以确定新的生物标志物，以确定哪些DCIS病例可能成为侵入性的，并改善患者的治疗。IDC中成纤维细胞的积累与疾病进展和生存率降低有关。虽然在DCIS中检测到成纤维细胞，但对其在DCIS进展中的作用知之甚少。我们试图确定1)DCIS成纤维细胞在转录组水平上是否与正常和IDC成纤维细胞相似或不同，以及2)DCIS成纤维细胞对乳腺癌进展的贡献。成纤维细胞进行转录组分析和通路分析。在现有的乳腺癌mRNA数据库中，通过组织阵列免疫染色进一步分析DCIS成纤维细胞相关基因。采用肾下包膜移植模型，将正常乳腺、DCIS和IDC组织成纤维细胞与DCIS.com乳腺癌细胞共移植。通过转录组分析，我们发现DCIS成纤维细胞具有细胞周期和运动相关基因PKMYT1、TGF-α、SFRP1和SFRP2的独特改变，这些基因通过独创性途径分析预测细胞生长和侵袭的增加。免疫染色分析显示，DCIS和IDC组织中基质源性PKMYT1、TGF-α的表达相应升高，SFRP1、SFRP2的表达相应降低。小鼠移植研究表明，DCIS成纤维细胞通过精氨酸酶-1+细胞募集增强乳腺癌的生长和侵袭。DCIS成纤维细胞在表型上不同于正常乳腺和IDC成纤维细胞，在乳腺癌生长、侵袭和骨髓细胞募集中发挥重要作用。这些研究为DCIS成纤维细胞在乳腺癌进展中的作用提供了新的见解，并确定了与DCIS进展到IDC相关的一些关键生物标志物，具有重要的临床意义。
As the most common form of pre-invasive breast cancer, ductal carcinoma in situ (DCIS) affects over 50,000 women in the US annually. Despite standardized treatment involving lumpectomy and radiation therapy, up to 25% of patients with DCIS experience disease recurrence often with invasive ductal carcinoma (IDC), indicating that a subset of patients may be under-treated. As most DCIS cases will not progress to invasion, many patients may experience over-treatment. By understanding the underlying processes associated with DCIS to IDC progression, we can identify new biomarkers to determine which DCIS cases may become invasive and improve treatment for patients. Accumulation of fibroblasts in IDC is associated with disease progression and reduced survival. While fibroblasts have been detected in DCIS, little is understood about their role in DCIS progression. We sought to determine 1) whether DCIS fibroblasts were similar or distinct from normal and IDC fibroblasts at the transcriptome level, and 2) the contributions of DCIS fibroblasts to breast cancer progression. Fibroblasts underwent transcriptome profiling and pathway analysis. Significant DCIS fibroblast-associated genes were further analyzed in existing breast cancer mRNA databases and through tissue array immunostaining. Using the sub-renal capsule graft model, fibroblasts from normal breast, DCIS and IDC tissues were co-transplanted with DCIS.com breast cancer cells. Through transcriptome profiling, we found that DCIS fibroblasts were characterized by unique alterations in cell cycle and motility related genes such as PKMYT1, TGF-α, SFRP1 and SFRP2, which predicted increased cell growth and invasion by Ingenuity Pathway Analysis. Immunostaining analysis revealed corresponding increases in expression of stromal derived PKMYT1, TGF-α and corresponding decreases in expression of SFRP1 and SFRP2 in DCIS and IDC tissues. Grafting studies in mice revealed that DCIS fibroblasts enhanced breast cancer growth and invasion associated with arginase-1+ cell recruitment. DCIS fibroblasts are phenotypically distinct from normal breast and IDC fibroblasts, and play an important role in breast cancer growth, invasion, and recruitment of myeloid cells. These studies provide novel insight into the role of DCIS fibroblasts in breast cancer progression and identify some key biomarkers associated with DCIS progression to IDC, with important clinical implications.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1073/pnas.2011342118
发表时间：
2021-01-19
影响因子：
11.1
作者：
Damaghi M;West J;Robertson-Tessi M;Xu L;Ferrall-Fairbanks MC;Stewart PA;Persi E;Fridley BL;Altrock PM;Gatenby RA;Sims PA;Anderson ARA;Gillies RJ
通讯作者：
Gillies RJ
影响因子：
2.5
作者：
Bernard S;Myers M;Fang WB;Zinda B;Smart C;Lambert D;Zou A;Fan F;Cheng N
通讯作者：
Cheng N
影响因子：
5.7
作者：
Fontenot E;Rossi E;Mumper R;Snyder S;Siamakpour-Reihani S;Ma P;Hilliard E;Bone B;Ketelsen D;Santos C;Patterson C;Klauber-DeMore N
通讯作者：
Klauber-DeMore N
影响因子：
7.7
作者：
Brion C;Lutz SM;Albert FW
通讯作者：
Albert FW