The Role of the Fox Gene in Breast Cancer Progression

Abstract

Forkhead box (FOX) genes are a family of transcription factors that participate in many biological activities, from early embryogenesis to the formation of organs, and from regulation of glucose metabolism to regulation of longevity. Given the extensive influence in the multicellular process, FOX family proteins are responsible for the progression of many types of cancers, especially lung cancer, breast cancer, prostate cancer, and other cancers. Breast cancer is the most common cancer among women, and 2.3 million women were diagnosed in 2020. So, various drugs targeting the FOX signaling pathway have been developed to inhibit breast cancer progression. While the role of the FOX family gene in cancer development has not received enough attention, discovering more potential drugs targeting the FOX signaling pathway is urgently demanded. Here, we review the main members in the FOX gene family and summarize their signaling pathway, including the regulation of the FOX genes and their effects on breast cancer progression. We hope this review will emphasize the understanding of the role of the FOX gene in breast cancer and inspire the discovery of effective anti-breast cancer medicines targeting the FOX gene in the future.

Keywords: breast cancer; drug resistance; forkhead box (FOX).

Figure 1

Structure of FOX TFs. FHD: Forkhead box domain; TAD: Transcriptionally Active Domain; NLS: Nuclear Localization Signal; LXL Motif: Leucine-X-Leucine Motif; NES: Nuclear Export Signal.

Figure 2

Regulation of FOXA1 and FOXA2, and their oncogene effects. During the progression of breast cancer, dysregulated oncogenes promote or repress the transcription of FOXA1 and FOXA2 genes, regulating their translocation between the nucleus and cytosol to upregulate the effects of FOXA1 and FOXA2 in transactivating downstream oncogenes. FOXA1 and FOXA2 are quite similar in structure, so they may have some overlapping in several pathways. Symbols: ↑ promote, ⊥ inhibit.

Figure 3

Regulation of FOXC1 and its oncogene effects. Oncogenic pathways mainly promote the transcription of FOXC1 to regulate its expression. Overexpressed FOXC1 acts as a transcription factor to transactive the expression of downstream oncogenes. Through the stimulation of the transcription of FOXC1, oncogenes can upregulate the downstream gene of FOXC1. Symbols: ↑ promote, ⊥ inhibit.

Figure 4

Oncogene effects of FOXF2. FOXF2 can act as both a tumor promoter and suppressor. The specific impact depends on the type of breast cancer and the particular situation. In general, FOXF2 exerts its dual function via oncogenic pathways and tumor-suppressive pathways. Symbols: ↑ promote, ⊥ inhibit.

Figure 5

Regulation of FOXM1 and its oncogene effects. Dysregulated factors target FOXM1 and eventually induce the deterioration of cancer. Overexpression of FOXM1 tends to transactive many oncogenes, which promote the proliferation, EMT, and metastasis of breast cancer. Mechanisms regulating FOXM1, including translation, translocation, phosphorylation, and ubiquitin. Symbols: ↑ promote, ⊥ inhibit.

Figure 6

Regulation and tumor suppressive effects of FOXO3. The activity and level of FOXO3 are negatively related to the malignancy degree of breast cancer. The pathways above the figure regulate FOXO3 activity and level. The specific mechanism includes acetylation, ubiquitination, and phosphorylation. The pathways below the figure illustrate how FOXO3 represses breast cancer. FOXO3a represses breast cancer by promoting the expression of tumor suppressors and repress the expression of oncogenes. Symbols: ↑ promote, ⊥ inhibit.