Clinicopathological Significances of Cancer Stem Cell-Associated HHEX Expression in Breast Cancer

Abstract

Aberrant expression of the transcription factor hematopoietic ally expressed homeobox/proline-rich homeodomain (HHEX/PRH) is implicated in numerous cancers. However, the association of HHEX with breast cancer (BC) remains unclear. In this study, HHEX mRNA and protein expression were analyzed using the Oncomine, UALCAN, GEPIA, TCGAportal, and HPA databases. We evaluated the effect of HHEX on clinicopathological parameters using Kaplan–Meier plotter, OncoLnc, TCGAportal, PROGgeneV2, and BC-GenExMiner. Western blotting was performed to compare the level of HHEX in breast samples of Tientsin Albino 2 mice, human breast precancerous lesions, benign breast tumors, and BC. The correlation between HHEX and cancer stem cells was investigated using the GEO (GSE52327 and GSE94865) and GEPIA datasets. Networks between HHEX and survival-related gene marker sets and microRNAs were analyzed using GEPIA, StarBase, and Cytoscape. Results of this study showed that HHEX expression in BC was significantly lower than those in breast precancerous lesions and benign breast tumors at both mRNA and protein levels. BC patients with lower HHEX expression had significantly worse overall survival and disease-free survival. Moreover, HHEX significantly affected the clinicopathology of BC. Specifically, low HHEX expression was correlated with the following groups of patients: age ≤51 years, ER-negative or PR-negative patients, HER-2 positive, triple-negative breast cancer, and basal-like BC. Immunohistochemical analysis of the breast samples showed significant differences of HHEX staining index (P < 0.001) among the three groups. To further investigate the mechanism, we determined the intersection of differentially expressed genes related to BC stem cells and those genes after HHEX expression was altered. This led to the identification of four potentially regulated genes-CXL12, BLNK, PAG1, and LPXN. Using StarBase and km-plotter, the negative regulation of HHEX expression and survival trends, including miR-130b, miR-30e, and miR-301b were joined into miRNA-HHEX-mRNA potential regulatory network. The abilities of proliferation, migration and invasion increased in MDA-MB-231 and BT-549 breast cancer cell lines after HHEX down expression and decreased after HHEX overexpression compared them in the control cells. In conclusion, these data suggest that HHEX expression is downregulated in BC and HHEX may regulate the development of BC through the stem cell-related genes.

Comparative Gene Signature of (−)-Oleocanthal Formulation Treatments in Heterogeneous Triple Negative Breast Tumor Models: Oncological Therapeutic Target Insights

“…HHEX overexpression can also regulate the transcription of vascular endothelial growth factor (VEGF) and TGFβ co-receptor endoglin, suppressing BC cell proliferation and migration [ 69 ]. Clinically, lower HHEX expression is correlated with disease-free survival in BC patients [ 70 ]. Low HHEX expression is common in TNBC and hormone-negative and basal-like BCs [ 70 ].…”

“…Clinically, lower HHEX expression is correlated with disease-free survival in BC patients [ 70 ]. Low HHEX expression is common in TNBC and hormone-negative and basal-like BCs [ 70 ]. Furthermore, β1,4-N-acetylgalactosaminyltransferase 2 (B4GALNT2) is a biosynthetic enzyme of histo-blood group antigens Sda antigen, a natural component of the red blood cells in the healthy colon of a vast majority of people [ 71 ].…”

Research progress of nanocarriers for gene therapy targeting abnormal glucose and lipid metabolism in tumors

“…Additionally, there are multiple carbohydrate metabolism pathways in cells (as shown in Figure 1 ), including anaerobic glycolysis, the tricarboxylic acid (TCA) cycle, gluconeogenesis, and the pentose phosphate pathway (PPP) (Zhang et al. 2020 ).…”

“…After downregulation of HHEX expression, metastasis, invasion, and proliferation of breast cancer cells was significantly higher than those of normal cell lines (Zhang et al. 2020 ). The same regulatory effect was also observed in cervical cancer, where the increase in miR-130b-5p (miR-130b-5p is a passenger strand of miR-130b) in cervical cancer stem cells downregulated ETS-like gene 1 (ELK1) expression.…”

“…MiR-204-5p regulates lipid synthesis by targeting SIRT1, and the two are negatively correlated (Zhang et al. 2020 ). It was also found that miR-204-5p inhibited lipogenesis by inhibiting adipose stem cell differentiation, and bioinformatics analysis revealed that miR-204-5p is a potential target for the regulation of lipogenesis (Li et al.…”