Hypoxia-inducible factor-1 in human breast and prostate cancer

Abstract

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.