FOXF2 differentially regulates expression of metabolic genes in non-cancerous and cancerous breast epithelial cells

Abstract

Forkhead box F2 (FOXF2) functions as a transcription factor and is critically involved in programming organogenesis and regulating epithelial-to-mesenchymal transition (EMT) and cell proliferation. We recently have revealed that FOXF2 can exert distinct functional effects on different molecular subtypes of breast cancer. We found that FOXF2 expression is epigenetically silenced in luminal breast cancers due to its tumor-suppressive role in DNA replication regulation. In contrast, FOXF2 is overexpressed in basal-like triple-negative breast cancers (TNBCs) due to its oncogenic role in promoting EMT. Although our and other studies have shown that FOXF2 dysregulation is critical for tumorigenesis of various tissue types, the role of FOXF2 in metabolic rewiring of cancer remains unknown. In this study, we analyzed our previous microarray data to understand the metabolic role of FOXF2 in non-cancerous and cancerous breast epithelial cells. Our studies showed that in non-cancerous breast epithelial cells FOXF2 can also play a dual role either in tumor suppression or in tumor promotion through regulating expression of tumor-suppressive and oncogenic metabolic genes. Furthermore, we found that FOXF2-regulated metabolic genes are not conserved between non-cancerous and cancerous breast epithelial cells and FOXF2 is involved in metabolic rewiring in breast cancer cells. This is the first report to explore the metabolic function of FOXF2 in breast cancer.

FOXF2 acts as a crucial molecule in tumours and embryonic development

“…found that FOXF2 can directly target FOXC2 and transcriptionally inhibit FOXC2 in BLBC cells. FOXC2mediated EMT may be another mechanism by which cancer cells initiate and maintain drug resistance 54 . Therefore, FOXF2 can achieve anticancer effects by inhibiting FOXC2, which suppresses the invasiveness and drug resistance of BLBC cells.…”

Forkhead box F2 as a novel prognostic biomarker and potential therapeutic target in human cancers prone to bone metastasis: a meta-analysis

“…The present meta-analysis systematically aggregated the data from 16 studies including 8461 cancer patients that assessed the relationship between FOXF2 levels and OS, DFS, RFS, CSS and DMFS. 14,[16][17][18][26][27][28][29][30][31][32][33][34][35][36][37] These current results demonstrated that FOXF2 might be a potentially promising prognostic biomarker. The upregulation of FOXF2 levels was independently associated with better OS (HR ¼ 0.66; 95% CI 0.51, 0.86; P ¼ 0.002) and DFS (HR ¼ 0.60; 95% CI 0.48, 0.76; P < 0.0001).…”

“…One dataset each evaluated the association between FOXF2 levels and RFS and DMFS for BC and one dataset examined the association between FOXF2 levels and CSS in ESCC. 18,28,35 The results from two studies indicated that elevated FOXF2 levels were associated with shorter RFS and DMFS among BC patients (HR ¼ 1.25; 95% CI 1.11, 1.39; HR ¼ 2.23; 95% CI 1.16, 3.12; respectively). However, in patients with ESCC, decreased FOXF2 levels were significantly correlated with an unfavourable CSS (HR ¼ 1.71; 95% CI 1.08, 2.71).…”

“…48 Previous research has examined the mechanism underlying the association between the levels of FOXF2 and poor prognosis in patients with multiple types of cancer (Table 3). 16,18,26,27,30,34,35,[49][50][51][52][53][54][55][56][57] Other studies suggested that the regulation of FOXF2 levels is involved in tumorigenesis, development and metastasis in breast cancer and other cancer types. 28,32 Studies suggest that FOXF2 may be dependent on different breast cancer subtypes, thereby affecting treatment response and prognosis of breast cancer patients.…”

“…28,32 Studies suggest that FOXF2 may be dependent on different breast cancer subtypes, thereby affecting treatment response and prognosis of breast cancer patients. 16,18 FOXF2 is known to be highly expressed in triplenegative/basal-like breast cancers and lowly expressed in luminal subtype breast cancers, while independently predicting poor prognosis in triple-negative breast cancer patients. 16 Bone metastasis is a process attributed to the loss of intercellular cohesion of s welling cells, cell migration, angiogenesis, entry into the humoral circulation, evasion of local immune responses and colonization of bone.…”