Kimbro K S, Simons J W
Department of Hematology and Oncology, Emory School of Medicine, Winship Cancer Institute, 1365 Clifton Road, NE, Atlanta, Georgia 30322, USA.
Endocr Relat Cancer. 2006 Sep;13(3):739-49. doi: 10.1677/erc.1.00728.
The tumor microenvironment is best characterized as a fluctuation of hypoxia and nutrient deprivation, which leads to epigenetic and genetic adaptation of clones and increased invasiveness and metastasis. In turn, these hypoxic adaptations make the tumors more difficult to treat and confer increased resistance to current therapies. Part of this adaptation is the regulation of gene products in response to hypoxia. Many of these hypoxia-regulated genes are mediated by the hypoxia-inducible factor 1 (HIF-1) complex, which is composed of a heterodimer pair of HIF-1alpha and HIF-1beta. This heterodimer binds to the promoter of hypoxia-responsive genes, while interacting with other transcription factors, such as p300, signal and transducer of transcription 3, and Redox effector factor 1/apurinic/apyrimidinic endonuclease. HIF-1alpha levels itself can be regulated by hypoxia transcriptionally and post-translationally through ubiquitination; but the magnitude of the response is modulated by several other pathways, including free radicals that affect crosstalk with HIF-1alpha/HIF-1beta transcriptional activities. HIF-1alpha has emerged as an important transcription factor in breast cancer and prostate cancer biology, and is expressed in the early stages of mammary and prostate carcinogenesis. Its expression is correlated with diagnostic and prognostic indicators for early relapse and metastatic disease, thus making HIF-1alpha a potential prognostic biomarker in proteomic assessments of breast and prostate cancers. The importance of HIF-1alpha in tumor progression makes it a logical target for chemoprevention strategies in patients at higher genetic risk of breast and prostate cancer with Cox 2 inhibitors or 2-methoxyestradiol, as well as a target for new approaches to inhibiting angiogenesis. The crosstalk between estrogen signaling pathways and HIF-1alpha is still not fully defined in breast cancer, but downstream estrogen receptor signaling may be a candidate for estrogen modulation of HIF-1alpha levels. In prostate cancer, androgens upregulate HIF-1alpha through androgen-regulated autocrine receptor tyrosine kinase receptor signaling. This review will put into perspective the role of HIF-1alpha in endocrine oncology and present new data on HIF-1alpha signaling and the potential for targeted therapies, including combinatory hormonal therapies.
肿瘤微环境的最佳特征是缺氧和营养剥夺的波动，这会导致克隆的表观遗传和基因适应，并增加侵袭性和转移能力。反过来，这些缺氧适应使肿瘤更难治疗，并增强了对当前疗法的抗性。这种适应的一部分是对缺氧反应的基因产物的调节。许多这些缺氧调节基因由缺氧诱导因子1（HIF-1）复合体介导，该复合体由HIF-1α和HIF-1β的异二聚体对组成。这种异二聚体与缺氧反应基因的启动子结合，同时与其他转录因子相互作用，如p300、转录信号转导子3和氧化还原效应因子1/无嘌呤/无嘧啶内切酶。HIF-1α水平本身可通过泛素化在转录和翻译后受到缺氧调节；但其反应的程度受到其他几种途径的调节，包括影响与HIF-1α/HIF-1β转录活性相互作用的自由基。HIF-1α已成为乳腺癌和前列腺癌生物学中的重要转录因子，并在乳腺和前列腺癌发生的早期阶段表达。其表达与早期复发和转移性疾病的诊断和预后指标相关，因此使HIF-1α成为乳腺癌和前列腺癌蛋白质组评估中的潜在预后生物标志物。HIF-1α在肿瘤进展中的重要性使其成为使用Cox 2抑制剂或2-甲氧基雌二醇对乳腺癌和前列腺癌遗传风险较高的患者进行化学预防策略的合理靶点，也是抑制血管生成新方法的靶点。雌激素信号通路与HIF-1α之间的相互作用在乳腺癌中仍未完全明确，但下游雌激素受体信号可能是雌激素调节HIF-1α水平的候选因素。在前列腺癌中，雄激素通过雄激素调节的自分泌受体酪氨酸激酶受体信号上调HIF-1α。本综述将阐述HIF-1α在内分泌肿瘤学中的作用，并展示关于HIF-1α信号传导以及靶向治疗潜力（包括联合激素治疗）的新数据。
