Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1.
Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1.
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DOI：
10.18632/oncotarget.9858
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发表时间：
2016-07-12
期刊：
影响因子：
--
通讯作者：
Marcato P
中科院分区：
文献类型：
--
作者：
Coyle KM;Murphy JP;Vidovic D;Vaghar-Kashani A;Dean CA;Sultan M;Clements D;Wallace M;Thomas ML;Hundert A;Giacomantonio CA;Helyer L;Gujar SA;Lee PW;Weaver IC;Marcato P
基于激素受体和其他基因表达的乳腺癌亚型可以决定患者预后和靶向治疗的潜在选择。在乳腺癌亚型中，基底样和低claudin亚型的肿瘤通常与较差的患者预后相关，主要被归类为三阴性乳腺癌（TNBC），不能用现有的激素受体靶向治疗。了解这些亚型的分子基础将有助于开发更有效的TNBC治疗方案。在这项研究中，我们将视黄酸受体应答者1 （RARRES1）作为一个范例来确定乳腺癌亚型是否决定蛋白质功能和基因表达调控。患者肿瘤数据集分析和代表五种乳腺癌亚型的26个细胞系面板的基因表达研究表明，RARRES1在基底样tnbc中表达最多。细胞增殖和肿瘤生长实验显示，RARRES1在TNBC中是一种肿瘤抑制因子。此外，基因表达研究、Illumina HumanMethylation450阵列和染色质免疫沉淀表明，在基底样乳腺癌中，由于启动子的低甲基化，RARRES1的表达得以保留。此外，癌症干细胞标志物醛脱氢酶1A3的表达也特异于基底样亚型，醛脱氢酶1A3为RARRES1转录提供所需的配体（视黄酸）。我们从功能上证明了启动子甲基化和维甲酸信号的结合以一种亚型特异性的方式决定了肿瘤抑制因子RARRES1的表达。这些发现为治疗诱导肿瘤抑制提供了先例，并为基底样乳腺癌患者的治疗干预提供了新的途径。
Breast cancer subtyping, based on the expression of hormone receptors and other genes, can determine patient prognosis and potential options for targeted therapy. Among breast cancer subtypes, tumors of basal-like and claudin-low subtypes are typically associated with worse patient outcomes, are primarily classified as triple-negative breast cancers (TNBC), and cannot be treated with existing hormone-receptor-targeted therapies. Understanding the molecular basis of these subtypes will lead to the development of more effective treatment options for TNBC. In this study, we focus on retinoic acid receptor responder 1 (RARRES1) as a paradigm to determine if breast cancer subtype dictates protein function and gene expression regulation. Patient tumor dataset analysis and gene expression studies of a 26 cell-line panel, representing the five breast cancer subtypes, demonstrate that RARRES1 expression is greatest in basal-like TNBCs. Cell proliferation and tumor growth assays reveal that RARRES1 is a tumor suppressor in TNBC. Furthermore, gene expression studies, Illumina HumanMethylation450 arrays, and chromatin immunoprecipitation demonstrate that expression of RARRES1 is retained in basal-like breast cancers due to hypomethylation of the promoter. Additionally, expression of the cancer stem cell marker, aldehyde dehydrogenase 1A3, which provides the required ligand (retinoic acid) for RARRES1 transcription, is also specific to the basal-like subtype. We functionally demonstrate that the combination of promoter methylation and retinoic acid signaling dictates expression of tumor suppressor RARRES1 in a subtype-specific manner. These findings provide a precedent for a therapeutically-inducible tumor suppressor and suggest novel avenues of therapeutic intervention for patients with basal-like breast cancer.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
254.7
作者：
DeSantis, Carol E.;Fedewa, Stacey A.;Jemal, Ahmedin
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Jemal, Ahmedin
影响因子：
64.5
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通讯作者：
Perou CM
影响因子：
3.7
作者：
Peng Z;Shen R;Li YW;Teng KY;Shapiro CL;Lin HJ
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Lin HJ
影响因子：
45.3
作者：
Parker, Joel S.;Mullins, Michael;Bernard, Philip S.
通讯作者：
Bernard, Philip S.