Human Epidermal Growth Factor Receptor-3 Expression Is Regulated at Transcriptional Level in Breast Cancer Settings by Junctional Adhesion Molecule-A via a Pathway Involving Beta-Catenin and FOXA1.
Human Epidermal Growth Factor Receptor-3 Expression Is Regulated at Transcriptional Level in Breast Cancer Settings by Junctional Adhesion Molecule-A via a Pathway Involving Beta-Catenin and FOXA1.
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DOI：
10.3390/cancers13040871
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发表时间：
2021-02-19
期刊：
影响因子：
5.2
通讯作者：
Hopkins AM
中科院分区：
文献类型：
--
作者：
Cruz RGB;Madden SF;Richards CE;Vellanki SH;Jahns H;Hudson L;Fay J;O'Farrell N;Sheehan K;Jirström K;Brennan K;Hopkins AM
来自人表皮生长因子受体（HER）蛋白家族的信号在许多癌症（包括乳腺癌）中增加。HER 2高乳腺癌可以用抗HER 2疗法成功治疗，但这些药物受到患者经常对它们产生耐药性的事实的限制。产生耐药性的一个常见机制是肿瘤获得高水平的HER 3家族成员。我们之前已经证明，一种名为JAM-A的蛋白质调节乳腺癌细胞中HER 2的水平，并与对HER 2靶向治疗的耐药性的发展有关。在这项研究中，我们首次表明JAM-A水平也调节HER 3的水平。使用乳腺癌细胞和组织模型并最终在患者组织材料中，我们提供了JAM-A通过涉及转录因子β-连环蛋白和FOXA 1的途径调节HER 3表达的证据。我们认为，JAM-A值得作为一种新的药物靶点进行进一步研究，因为它有可能减少HER 3致瘤信号传导，并抵消对HER 2靶向治疗的耐药性。 靶向人表皮生长因子受体-2（HER 2）的乳腺癌治疗的成功受到包括HER 3上调在内的机制导致的耐药性发展的限制。已经报道了HER 2表达和对HER 2靶向治疗的耐药性可以通过连接粘附分子-A（JAM-A）调节，本研究调查了JAM-A是否调节HER 3表达。乳腺癌细胞中JAM-A的表达改变用于测试体外和半体内对HER 3及其效应物的表达作用，以及相关的功能行为。通过JAM-A鉴定并测试HER 3转录因子的调节。最后，使用患者组织微阵列来询问连接JAM-A和HER 3的推定途径组分之间的连接。这项研究首次揭示了HER 3及其效应物在乳腺癌细胞系中通过JAM-A在基因/蛋白质表达水平上进行调节;在体外和半体内模型中具有功能性后果。在生物信息学、细胞和患者组织模型中，这与JAM-A通过涉及β-连环蛋白的途径调节HER 3转录因子FOXA 1相关。我们的数据表明了一种新的模型，即JAM-A表达调节β-catenin定位，进而调节FOXA 1表达，这可能驱动HER 3基因转录。JAM-A作为一种新的靶点值得研究，以防止在对HER 2靶向治疗产生耐药性期间HER 3上调，或减少HER 3依赖性致瘤信号传导。
Signaling from the human epidermal growth factor receptor (HER) family of proteins increases in many cancers, including breast. HER2-high breast cancers are successfully treated with anti-HER2 therapies, but these drugs are limited by the fact that patients frequently develop resistance to them. One common mechanism by which resistance develops is when tumors acquire high levels of a family member called HER3. We had previously shown that a protein called JAM-A regulates the level of HER2 in breast cancer cells, and is associated with the development of resistance to HER2-targeted therapies. In this study we show for the first time that JAM-A levels also regulate those of HER3. Using breast cancer cell and tissue models and culminating in patient tissue material, we provide evidence that JAM-A regulates HER3 expression via a pathway involving the transcription factors β-catenin and FOXA1. We suggest that JAM-A merits future investigation as a novel drug target for its potential to reduce HER3 tumorigenic signaling and to offset the development of resistance to HER2-targeted therapies. The success of breast cancer therapies targeting the human epidermal growth factor receptor-2 (HER2) is limited by the development of drug resistance by mechanisms including upregulation of HER3. Having reported that HER2 expression and resistance to HER2-targeted therapies can be regulated by Junctional Adhesion Molecule-A (JAM-A), this study investigated if JAM-A regulates HER3 expression. Expressional alteration of JAM-A in breast cancer cells was used to test expressional effects on HER3 and its effectors, alongside associated functional behaviors, in vitro and semi-in vivo. HER3 transcription factors were identified and tested for regulation by JAM-A. Finally a patient tissue microarray was used to interrogate connections between putative pathway components connecting JAM-A and HER3. This study reveals for the first time that HER3 and its effectors are regulated at gene/protein expression level by JAM-A in breast cancer cell lines; with functional consequences in in vitro and semi-in vivo models. In bioinformatic, cellular and patient tissue models, this was associated with regulation of the HER3 transcription factor FOXA1 by JAM-A via a pathway involving β-catenin. Our data suggest a novel model whereby JAM-A expression regulates β-catenin localization, in turn regulating FOXA1 expression, which could drive HER3 gene transcription. JAM-A merits investigation as a novel target to prevent upregulation of HER3 during the development of resistance to HER2-targeted therapies, or to reduce HER3-dependent tumorigenic signaling.
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DOI：
10.1186/s13058-018-1064-1
发表时间：
2018-11-20
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Leech AO;Vellanki SH;Rutherford EJ;Keogh A;Jahns H;Hudson L;O'Donovan N;Sabri S;Abdulkarim B;Sheehan KM;Kay EW;Young LS;Hill ADK;Smith YE;Hopkins AM
通讯作者：
Hopkins AM
DOI：
10.1073/pnas.060025397
发表时间：
2000-04-11
影响因子：
11.1
作者：
Lin, SY;Xia, WY;Hung, MC
通讯作者：
Hung, MC
DOI：
10.1053/ejso.1999.1017
发表时间：
2001-02-01
期刊：
EUROPEAN JOURNAL OF SURGICAL ONCOLOGY
影响因子：
--
作者：
Karayiannakis, AJ;Nakopoulou, L;Pignatelli, M
通讯作者：
Pignatelli, M
影响因子：
4.7
作者：
Clarke, Colin;Madden, Stephen F.;Clynes, Martin
通讯作者：
Clynes, Martin
影响因子：
64.5
作者：
Lupien, Mathieu;Eeckhoute, Jerome;Brown, Myles
通讯作者：
Brown, Myles