Abstract
Cell-cell adhesion molecule cadherin-11(CDH11) is preferentially expressed in basal-like breast cancer cells and facilitates breast cancer cell migration by promoting small GTPase Rac activity. However, how the expression of CDH11 is regulated in breast cancer cells is not understood. Here, we show that CDH11 is transcriptionally controlled by homeobox C8 (HOXC8) in human breast cancer cells. HOXC8 serves as a CDH11-specific transcription factor and binds to the site of nucleotides -196 to -191 in the CDH11 promoter. Depletion of HOXC8 leads to the decrease in anchorage-independent cell growth, cell migration/invasion and spontaneous metastasis of breast cancer cells; however, suppressed tumorigenic events were fully rescued by ectopic CDH11 expression in HOXC8-knockdown cells. These results indicate that HOXC8 impacts breast tumorigenesis through CDH11. The analysis of publically available human breast tumor microarray gene expression database demonstrates a strong positive linear association between HOXC8 and CDH11 expression ( = 0.801, p < 0.001). Survival analysis (Kaplan-Meier method, log-rank test) show that both high HOXC8 and CDH11 expression correlate with poor recurrence-free survival rate of patients. Together, our study suggests that HOXC8 promotes breast tumorigenesis by maintaining high level of CDH11 expression in breast cancer cells.
Highlights
IntroductionHomeobox C8 (HOXC8)-null mice exhibit neuromuscular defects in forelimb and skeletal defects in the ribs and vertebrae of the thorax [2] while overexpression of a HOXC8 transgene causes cartilage defects with an accumulation of proliferating chondrocytes and reduced maturation in skeletal elements [3]
Homeobox C8 (HOXC8) is one of the 39-member HOX family proteins [1]
We previously reported that knockdown of HOXC8 led to the reduction in Cadherin 11 (CDH11) expression in invasive breast cancer cells [22]
Summary
HOXC8-null mice exhibit neuromuscular defects in forelimb and skeletal defects in the ribs and vertebrae of the thorax [2] while overexpression of a HOXC8 transgene causes cartilage defects with an accumulation of proliferating chondrocytes and reduced maturation in skeletal elements [3]. Recent studies have linked HOXC8 into the tumorigenesis of various cancer types. HOXC8 expression is selectively turned on in human cervix cancer cells [5] and is associated with the loss of tumor differentiation in human prostate cancer cells [6]. We showed that HOXC8 level is elevated in invasive/metastatic breast tumor cell lines and its presence is required for breast cancer cell migration and metastasis [7]. HOXC8 was reported to influence the expression of a set of genes important for cell adhesion, migration and apoptosis [8,9]. It is of our interest to investigate whether one or more of www.impactjournals.com/oncotarget these genes are functionally critical for tumorigenic events elicited by HOXC8
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