An integrated genomic approach identifies persistent tumor suppressive effects of transforming growth factor-β in human breast cancer.
An integrated genomic approach identifies persistent tumor suppressive effects of transforming growth factor-β in human breast cancer.
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DOI：
10.1186/bcr3668
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发表时间：
2014-06-02
期刊：
影响因子：
--
通讯作者：
Wakefield LM
中科院分区：
文献类型：
--
作者：
Sato M;Kadota M;Tang B;Yang HH;Yang YA;Shan M;Weng J;Welsh MA;Flanders KC;Nagano Y;Michalowski AM;Clifford RJ;Lee MP;Wakefield LM
转化生长因子-β（TGF-βs）在乳腺癌中发挥双重作用，具有背景依赖性肿瘤抑制或促癌作用。TGF-β拮抗剂在早期临床肿瘤学试验中显示出中和促癌作用的前景。然而，目前还没有办法确定TGF-β的肿瘤抑制作用在手术和治疗时是否仍在人类乳腺肿瘤中发挥作用，这种情况可能导致不良治疗反应。使用证实TGF-β的双重作用的乳腺癌进展模型，应用启动子范围的染色质免疫沉淀和转录组学方法来鉴定TGF-β调节基因的核心组，其仅特异性地反映该途径的肿瘤抑制臂。使用临床乳腺癌数据集中的生物信息学分析和肿瘤异种移植物中的敲除验证方法研究了该特征的临床意义和基础生物学。TGF-β驱动的肿瘤抑制高度依赖于Smad 3，并且鉴定了特异性富集参与肿瘤抑制的Smad 3靶基因。Smad 3结合模式反映了预先存在的活性染色质景观，并且靶基因在体外和体内经常以相反的方向调节，突出了TGF-β作用的强背景性。体内加权TGF-β/Smad 3肿瘤抑制标记与雌激素受体阳性乳腺癌队列的良好结局相关。TGF-β/Smad 3对细胞增殖、分化和ephrin信号传导的作用有助于观察到的肿瘤抑制。TGF-β的肿瘤抑制作用在一些乳腺癌患者手术时持续存在，并影响临床结果。精心定制的体外/体内基因组方法可以鉴定这些患者，以排除TGF-β拮抗剂治疗。
Transforming growth factor-βs (TGF-βs) play a dual role in breast cancer, with context-dependent tumor-suppressive or pro-oncogenic effects. TGF-β antagonists are showing promise in early-phase clinical oncology trials to neutralize the pro-oncogenic effects. However, there is currently no way to determine whether the tumor-suppressive effects of TGF-β are still active in human breast tumors at the time of surgery and treatment, a situation that could lead to adverse therapeutic responses. Using a breast cancer progression model that exemplifies the dual role of TGF-β, promoter-wide chromatin immunoprecipitation and transcriptomic approaches were applied to identify a core set of TGF-β-regulated genes that specifically reflect only the tumor-suppressor arm of the pathway. The clinical significance of this signature and the underlying biology were investigated using bioinformatic analyses in clinical breast cancer datasets, and knockdown validation approaches in tumor xenografts. TGF-β-driven tumor suppression was highly dependent on Smad3, and Smad3 target genes that were specifically enriched for involvement in tumor suppression were identified. Patterns of Smad3 binding reflected the preexisting active chromatin landscape, and target genes were frequently regulated in opposite directions in vitro and in vivo, highlighting the strong contextuality of TGF-β action. An in vivo-weighted TGF-β/Smad3 tumor-suppressor signature was associated with good outcome in estrogen receptor-positive breast cancer cohorts. TGF-β/Smad3 effects on cell proliferation, differentiation and ephrin signaling contributed to the observed tumor suppression. Tumor-suppressive effects of TGF-β persist in some breast cancer patients at the time of surgery and affect clinical outcome. Carefully tailored in vitro/in vivo genomic approaches can identify such patients for exclusion from treatment with TGF-β antagonists.
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影响因子：
3.7
作者：
Kadota M;Yang HH;Gomez B;Sato M;Clifford RJ;Meerzaman D;Dunn BK;Wakefield LM;Lee MP
通讯作者：
Lee MP
DOI：
10.1073/pnas.0912708107
发表时间：
2010-04-13
影响因子：
11.1
作者：
Gatza, Michael L.;Lucas, Joseph E.;Nevins, Joseph R.
通讯作者：
Nevins, Joseph R.
影响因子：
11.2
作者：
Bierie, Brian;Stover, Daniel G.;Moses, Harold L.
通讯作者：
Moses, Harold L.
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
3.7
作者：
Kennedy BA;Deatherage DE;Gu F;Tang B;Chan MW;Nephew KP;Huang TH;Jin VX
通讯作者：
Jin VX