HOXC8 promotes breast tumorigenesis by transcriptionally facilitating cadherin-11 expression

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 (ρ = 0.801, p < 0.001). Survival analysis (Kaplan-Meier method, log-rank test) shows 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.

HOXC8 (homeobox C8)

“…Moreover, the analysis of publically available human breast tumor microarray gene expression database demonstrates a strong positive linear association between HOXC8 and CDH11 expression (R = 0.801, p < 0.001). Survival analysis (Kaplan-Meier method, log-rank test) show that both high HOXC8 and CDH11 expression correlates with poor recurrence-free survival rate of patients (Li et al, 2014). Together, these findings suggest that HOXC8 promotes breast tumorigenesis by maintaining high level of CDH11 expression in breast cancer cells.…”

“…Ectopic HOXC8 expression induces Cdh11 expression and promotes breast tumorigenesis (Li et al, 2012). Importantly, forced Cdh11 expression reverses the inhibitory effect in breast tumorigenesis elicited by HOXC8 knockdown (Li et al, 2014). Moreover, the analysis of publically available human breast tumor microarray gene expression database demonstrates a strong positive linear association between HOXC8 and CDH11 expression (R = 0.801, p < 0.001).…”

“…The gene is also expressed in both the neural tube and the somites in the prospective thorax (Pollock et al, 1992;Shashikant and Ruddle, 1996). Cancers: Elevated HOXC8 expression is detected in breast cancer (Li et al, 2014;Li et al, 2010), cervical cancer (Alami et al, 1999), prostate cancer (Waltregny et al, 2002), esophageal cancer (Du et al, 2014), pancreatic cancer (Adwan et al, 2011). Organs: HOXC8 is expressed in hematopoietic organs, brain, breast, placenta, liver, bone marrow, kidney, intestine and nervous systems, etc.…”

“…In response to bone morphogenetic protein (BMP) stimulation, HOXC8 activates the transcription of osteopontin (OPN) by interacting with Smad1 (Shi et al, 1999). In breast cancer cells, HOXC8 functions as a transcription factor to regulate cadherin 11 (Cdh11) transcription (Li et al, 2014;Li et al, 2011). ChIP assays demonstrate that HOXC8 can bind to the promoter of target genes including NCAM (neural cell adhesion molecule), PEDF (pigment epithelium-derived factor), ZAC1 (the zinc finger protein regulator of apoptosis) and PCNA (proliferating cell nuclear antigen) Min et al, 2010).…”

Cadherin-11 expression is upregulated in invasive human breast cancer

“…This event is part of a process that is vital to malignant change, the epithelial-mesenchymal transition (EMT). EMT is a key biologic process that was initially identified as a developmental program that enables polarized epithelial cells to acquire a motile mesenchymal phenotype (13–17,19,20). This transition results in a more invasive and metastatic phenotype (15–17,19).…”