Neuronatin is a modifier of estrogen receptor-positive breast cancer incidence and outcome.
Neuronatin is a modifier of estrogen receptor-positive breast cancer incidence and outcome.
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DOI：
10.1007/s10549-019-05307-8
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发表时间：
2019-08
影响因子：
3.8
通讯作者：
Flister, Michael J.
中科院分区：
文献类型：
--
作者：
Plasterer, Cody;Tsaih, Shirng-Wern;Peck, Amy R.;Chervoneva, Inna;O'Meara, Caitlin;Sun, Yunguang;Lemke, Angela;Murphy, Dana;Smith, Jennifer;Ran, Sophia;Kovatich, Albert J.;Hooke, Jeffrey A.;Shriver, Craig D.;Hu, Hai;Mitchell, Edith P.;Bergom, Carmen;Joshi, Amit;Auer, Paul;Prokop, Jeremy;Rui, Hallgeir;Flister, Michael J.
了解乳腺癌生存的分子介质对于准确的疾病预后和改进治疗至关重要。在这里，我们将 Neuronatin (NNAT) 确定为雌激素受体-α (ER+) 乳腺癌的新型抗增殖调节剂。通过在致癌物诱发乳腺癌的大鼠模型中进行同源作图，鉴定出含有乳腺癌修饰因子的基因组区域。通过 RNAseq 分析来自易感和抗性同源基因的肿瘤，以确定候选基因。根据三个乳腺癌患者队列的共识，根据与结果的相关性对候选人进行优先排序。 NNAT 在 ER+ 乳腺癌系（T47D 和 ZR75）中转基因表达，然后进行转录组和表型表征。我们在大鼠 3 号染色体 (142–178 Mb) 上发现了一个可以改变乳腺肿瘤发生率的区域。乳腺肿瘤的 RNAseq 将候选列表缩小到三个差异表达基因：NNAT、SLC35C2 和 FAM210B。 NNAT mRNA 和蛋白质也与人类乳腺癌患者的生存相关。在侵袭性 ER+ 乳腺癌患者的单变量分析中，NNAT 蛋白的定量免疫组织化学显示与生存呈负相关（训练队列：n = 444，HR = 0.62，p = 0.031；验证队列：n = 430，HR = 0.48，p = 0.004）。经过多变量调整后，NNAT 也被认为是生存的独立预测因子（HR = 0.64，p = 0.038）。 NNAT 显着减少 ER+ 乳腺癌细胞的增殖和迁移，这与多种相关途径表达的改变相一致。总的来说，这些数据表明 NNAT 是细胞增殖和迁移的新型介质，与降低致瘤潜力和延长患者生存期相关。
Understanding the molecular mediators of breast cancer survival is critical for accurate disease prognosis and improving therapies. Here, we identified Neuronatin (NNAT) as a novel antiproliferative modifier of estrogen receptor-alpha (ER+) breast cancer. Genomic regions harboring breast cancer modifiers were identified by congenic mapping in a rat model of carcinogen-induced mammary cancer. Tumors from susceptible and resistant congenics were analyzed by RNAseq to identify candidate genes. Candidates were prioritized by correlation with outcome, using a consensus of three breast cancer patient cohorts. NNAT was transgenically expressed in ER+ breast cancer lines (T47D and ZR75), followed by transcriptomic and phenotypic characterization. We identified a region on rat chromosome 3 (142–178 Mb) that modified mammary tumor incidence. RNAseq of the mammary tumors narrowed the candidate list to three differentially expressed genes: NNAT, SLC35C2, and FAM210B. NNAT mRNA and protein also correlated with survival in human breast cancer patients. Quantitative immunohistochemistry of NNAT protein revealed an inverse correlation with survival in a univariate analysis of patients with invasive ER+ breast cancer (training cohort: n = 444, HR = 0.62, p = 0.031; validation cohort: n = 430, HR = 0.48, p = 0.004). NNAT also held up as an independent predictor of survival after multivariable adjustment (HR = 0.64, p = 0.038). NNAT significantly reduced proliferation and migration of ER+ breast cancer cells, which coincided with altered expression of multiple related pathways. Collectively, these data implicate NNAT as a novel mediator of cell proliferation and migration, which correlates with decreased tumorigenic potential and prolonged patient survival.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
3.7
作者：
Khaidakov M;Mitra S;Kang BY;Wang X;Kadlubar S;Novelli G;Raj V;Winters M;Carter WC;Mehta JL
通讯作者：
Mehta JL
影响因子：
5.2
作者：
Lin, Hsuan-Hwai;Bell, Esther;Uwanogho, Dafe;Perfect, Leo W.;Noristani, Harun;Bates, Thomas J. D.;Snetkov, Vladimir;Price, Jack;Sun, Yuh-Man
通讯作者：
Sun, Yuh-Man
影响因子：
4.8
作者：
Joe, Myung Kuk;Lee, Hyo Jung;Jung, Myeong Ho
通讯作者：
Jung, Myeong Ho
影响因子：
3.7
作者：
Oyang EL;Davidson BC;Lee W;Poon MM
通讯作者：
Poon MM