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

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.

Therapeutic Targeting of Hypoxia-Inducible Factors in Cancer

“…Research has shown that higher levels of HIF-1α expression are associated with poorer survival outcomes, including decreased Disease-Free Survival (DFS) and Overall Survival (OS). These findings highlight the potential of HIF-1α as a prognostic biomarker, aiding in risk stratification and treatment planning for breast cancer patients [50].…”

Expression profile of interleukin-6, 4-hydroxy-2-nonenal, and hypoxia-inducible factor 1-α in women with breast cancer and their association with clinicopathological parameters

“…Hypoxia is a common feature associated with many types of cancer, and it is an ever-present condition in the tumour environment due to the rapid growth of tumour cells that are not supported by an adequate blood supply. This state may impact on the production of HIF-1α, a transcription factor implicated in carcinogenesis, tumour growth, and other biological mechanisms [ 66 , 67 ]. In BC, hypoxia is known to play a crucial role in cancer progression and cancer treatment failure [ 68 ].…”

The Clinical Applications of Hypoxia-Inducible Factor-1Alpha (HIF-1α)

“…In gastric cancer, HIF-1α has been found to promote proliferation and angiogenesis, resulting in the growth of gastric cancer cells [17]. Overexpression in breast cancer also contributes to larger tumor size and its correlation with lower survival is confirmed [18]. However, in terms of patients with non-small-cell lung cancer or head and neck cancer, the opposite result appears.…”

“…The experiment indicates that HIF-1α inhibition is an accessible method to promote anti-tumor immunity [21]. In chemotherapy, the function of drugs can be damaged by HIF-1α, causing chemo-resistance [17,18]. It is possible that HIF-1α upregulation impairs cancer therapy and its inhibition can be admitted in new treatment.…”