Malorni Luca, Giuliano Mario, Migliaccio Ilenia, Wang Tao, Creighton Chad J, Lupien Mathieu, Fu Xiaoyong, Hilsenbeck Susan G, Healy Nuala, De Angelis Carmine, Mazumdar Abhijit, Trivedi Meghana V, Massarweh Suleiman, Gutierrez Carolina, De Placido Sabino, Jeselsohn Rinath, Brown Myles, Brown Powel H, Osborne C Kent, Schiff Rachel
Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Sandro Pitigliani Medical Oncology Unit and Translational Research Unit, Oncology Department, Hospital of Prato, Prato, Italy.
Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, Naples, Italy.
Mol Cancer Res. 2016 May;14(5):470-81. doi: 10.1158/1541-7786.MCR-15-0423. Epub 2016 Mar 10.
The transcription factor AP-1 is downstream of growth factor (GF) receptors (GFRs) and stress-related kinases, both of which are implicated in breast cancer endocrine resistance. Previously, we have suggested that acquired endocrine resistance is associated with increased activity of AP-1 in an in vivo model. In this report, we provide direct evidence for the role of AP-1 in endocrine resistance. First, significant overlap was found between genes modulated in tamoxifen resistance and a gene signature associated with GF-induced estrogen receptor (ER) cistrome. Interestingly, these overlapping genes were enriched for key signaling components of GFRs and stress-related kinases and had AP-1 motifs in their promoters/enhancers. Second, to determine a more definitive role of AP-1 in endocrine resistance, AP-1 was inhibited using an inducible dominant-negative (DN) cJun expressed in MCF7 breast cancer cells in vitro and in vivo AP-1 blockade enhanced the antiproliferative effect of endocrine treatments in vitro, accelerated xenograft tumor response to tamoxifen and estrogen deprivation in vivo, promoted complete regression of tumors, and delayed the onset of tamoxifen resistance. Induction of DN-cJun after the development of tamoxifen resistance resulted in dramatic tumor shrinkage, accompanied by reduced proliferation and increased apoptosis. These data suggest that AP-1 is a key determinant of endocrine resistance by mediating a global shift in the ER transcriptional program.
AP-1 represents a viable therapeutic target to overcome endocrine resistance. Mol Cancer Res; 14(5); 470-81. ©2016 AACR.
转录因子AP-1位于生长因子（GF）受体（GFR）和应激相关激酶的下游，这两者均与乳腺癌内分泌抵抗有关。此前，我们曾提出在体内模型中，获得性内分泌抵抗与AP-1活性增加相关。在本报告中，我们提供了AP-1在内分泌抵抗中作用的直接证据。首先，在他莫昔芬耐药中调节的基因与与GF诱导的雌激素受体（ER）顺反组相关的基因特征之间发现了显著重叠。有趣的是，这些重叠基因富含GFR和应激相关激酶的关键信号成分，并且在其启动子/增强子中具有AP-1基序。其次，为了确定AP-1在内分泌抵抗中更明确的作用，在体外和体内使用在MCF7乳腺癌细胞中表达的可诱导显性负性（DN）cJun抑制AP-1。AP-1阻断增强了体外内分泌治疗的抗增殖作用，加速了体内异种移植肿瘤对他莫昔芬和雌激素剥夺的反应，促进了肿瘤的完全消退，并延迟了他莫昔芬耐药的发生。在他莫昔芬耐药发展后诱导DN-cJun导致肿瘤显著缩小，同时增殖减少和凋亡增加。这些数据表明，AP-1通过介导ER转录程序的整体转变，是内分泌抵抗的关键决定因素。
AP-1是克服内分泌抵抗的一个可行治疗靶点。《分子癌症研究》；14(5)；470 - 81。©2016美国癌症研究协会。
