Abstract
Cellular adaptive mechanisms are crucial for tumorigenesis and a common feature in solid tumor progression. Hypoxia-inducible factor-1α (HIF-1α) facilitates the biological response to hypoxia, advancing angiogenesis and metastatic potential of the tumor. The peroxisome proliferator–activated receptor γ coactivators 1α (PGC-1α) enhances mitochondrial biogenesis, favored by migratory/invasive cancer cells. We conducted a prospective, long-term follow up study to determine whether HIF-1α and PGC-1α can be implemented as predictive biomarker in breast cancer. HIF-1α and PGC-1α plasma concentrations were measured in patients and in healthy controls by enzyme linked immune sorbent assay. Breast cancer patients had significantly higher HIF-1α and PGC-1α levels, which correlated with clinicopathological features, overall with more aggressive cancer characteristics. Disease free and overall survival of breast cancer patients with high HIF-1α and PGC-1α were significantly poorer than in patients with low plasma levels. In multivariate analysis, high amount of PGC-1α showed independent prognostic value. Our data suggests that HIF-1α and PGC-1α may be promising, noninvasive, biomarkers with a high potential for future clinical implication to identify subgroups of patients with poorer prognosis and to indicate early, subclinical metastasis.
Highlights
Scientific evidence confirms that tumor microenvironment influences tumorigenesis and tumor progression
A total of 297 human plasma samples were assayed by ELISA to measure the plasma levels of Hypoxia-inducible factor1α (HIF-1α) and PGC-1α
Mean HIF-1α plasma levels was 10.197ng/dl, while the mean of PGC-1α plasma levels was 246.502ng/dl
Summary
Scientific evidence confirms that tumor microenvironment influences tumorigenesis and tumor progression. Cancer itself induces hypoxia due to inflammatory processes, which activates a cascade of cytokines and chemokines [4,5,6]. Hypoxic cancer tissue microenvironment is closely related to tumor growth, tumor development, metastasis, therapy response and prognosis [7,8,9,10]. Cellular reaction to oxygen level is, in part, induced by hypoxia-inducible, oxygen-sensitive transcription factor HIF. This driving mediator consists of subunit proteins, which experience post-translational modifications in hypoxic conditions [11,12,13]. Hypoxia-inducible factor1α (HIF-1α) is the functional subunit determining its activity [14, 15]. Under low concentrations of oxygen, HIF-1α is stabilized and its intracellular levels increase since ubiquitination and degradation is blocked [16]
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