Hypoxia in Breast Cancer—Scientific Translation to Therapeutic and Diagnostic Clinical Applications

Abstract

Breast cancer has been the leading cause of female cancer deaths for decades. Intratumoral hypoxia, mainly caused by structural and functional abnormalities in microvasculature, is often associated with a more aggressive phenotype, increased risk of metastasis and resistance to anti-malignancy treatments. The response of cancer cells to hypoxia is ascribed to hypoxia-inducible factors (HIFs) that activate the transcription of a large battery of genes encoding proteins promoting primary tumor vascularization and growth, stromal cell recruitment, extracellular matrix remodeling, cell motility, local tissue invasion, metastasis, and maintenance of the cancer stem cell properties. In this review, we summarized the role of hypoxia specifically in breast cancer, discuss the prognostic and predictive value of hypoxia factors, potential links of hypoxia and endocrine resistance, cancer hypoxia measurements, further involved mechanisms, clinical application of hypoxia-related treatments and open questions.

(Im)maturity in Tumor Ecosystem

“…HIF-1 acts as a key role for CSC generation and maintenance ( 181 ). Hypoxia possibly retains CSCs in an undifferentiated state, and allowing only differentiation of cancer cells ( 182 ). Bulle and colleagues in a study evaluated the impact of the anti-septic drug acriflavine on xenograft pancreatic cancer.…”

Design, Synthesis and In-Vitro Biological Evaluation of Antofine and Tylophorine Prodrugs as Hypoxia-Targeted Anticancer Agents

“…Additionally, hypoxia induces metastasis [ 25 ], promotes angiogenesis and vasculogenesis [ 26 , 27 ], and enhances invasiveness [ 28 ]. Given the important role of hypoxia in tumor development and progression, and given its relative absence in healthy tissues [ 29 ], hypoxia represents an attractive therapeutic target [ 22 , 30 , 31 , 32 ]. The main approach to targeting hypoxia consists of the development of bioreductive prodrugs that can be activated in hypoxic tissues by enzymatic reduction [ 33 , 34 , 35 , 36 ].…”

Identification of Novel Endogenous Controls for qPCR Normalization in SK-BR-3 Breast Cancer Cell Line

“…Hypoxia is one of the principal drivers of tumor progression and growth in vivo. The presence of hypoxic conditions in the cancer microenvironment is not only a recognized event in cancer development but also is sustained by the cancer cells themselves, secondary to the inflammatory processes [52][53][54]. Such a condition in the local tumor microenvironment is necessary to induce angiogenesis and release of growth factors whilst inducing structural and functional damage to the healthy surrounding tissue [54].…”

“…The presence of hypoxic conditions in the cancer microenvironment is not only a recognized event in cancer development but also is sustained by the cancer cells themselves, secondary to the inflammatory processes [52][53][54]. Such a condition in the local tumor microenvironment is necessary to induce angiogenesis and release of growth factors whilst inducing structural and functional damage to the healthy surrounding tissue [54]. It is estimated that about 1.5% of the whole human genome is transcriptionally responsive to hypoxia, thereby affecting gene expression [55].…”