The Role of Hypoxia-Inducible Factor Isoforms in Breast Cancer and Perspectives on Their Inhibition in Therapy

SIMPLE SUMMARY: In many types of cancers, the activity of the hypoxia-inducible factors enhances hallmarks such as suppression of the immune response, altered metabolism, angiogenesis, invasion, metastasis, and more. As a result of observing these features, HIFs became attractive targets in designing anticancer therapy. The lack of effective breast treatment based on HIFs inhibitors and the elusive role of those factors in this type of cancer raises the concern wheter targeting hypoxia-inducible factors is the right path. Results of the study on breast cancer cell lines suggest the need to consider aspects like HIF-1α versus HIF-2α isoforms inhibition, double versus singular isoform inhibition, different hormone receptors status, metastases, and perhaps different not yet investigated issues. In other words, targeting hypoxia-inducible factors in breast cancers should be preceded by a better understanding of their role in this type of cancer. The aim of this paper is to review the role, functions, and perspectives on hypoxia-inducible factors inhibition in breast cancer. ABSTRACT: Hypoxia is a common feature associated with many types of cancer. The activity of the hypoxia-inducible factors (HIFs), the critical element of response and adaptation to hypoxia, enhances cancer hallmarks such as suppression of the immune response, altered metabolism, angiogenesis, invasion, metastasis, and more. The HIF-1α and HIF-2α isoforms show similar regulation characteristics, although they are active in different types of hypoxia and can show different or even opposite effects. Breast cancers present several unique ways of non-canonical hypoxia-inducible factors activity induction, not limited to the hypoxia itself. This review summarizes different effects of HIFs activation in breast cancer, where areas such as metabolism, evasion of the immune response, cell survival and death, angiogenesis, invasion, metastasis, cancer stem cells, and hormone receptors status have been covered. The differences between HIF-1α and HIF-2α activity and their impacts are given special attention. The paper also discusses perspectives on using hypoxia-inducible factors as targets in anticancer therapy, given current knowledge acquired in molecular studies.