Alterations of the HBP1 Transcriptional Repressor Are Associated with Invasive Breast Cancer

Abstract

Invasive breast cancer has a high risk of recurrence to incurable disease and needs improved prognostic and therapeutic tools. Our work combines clinical and molecular analyses to show that the transcriptional repressor HBP1 may be a new target for invasive breast cancer. Previous work indicated that HBP1 regulated proliferation and senescence and inhibited Wnt signaling. Two of these functions have been associated with invasive breast cancer. In 76 breast tumors, we identified 10 HBP1 mutations/variants that were associated with fully invasive breast cancer. In a separate analysis, we found that a subset of invasive breast cancer specimens also had reduced HBP1 mRNA levels. These clinical correlations suggested that mutation or reduction of HBP1 occurs in invasive breast cancer and that HBP1 might regulate the proliferation and invasiveness of this breast cancer type. Analysis of the HBP1 mutants showed they were functionally defective for suppressing Wnt signaling. To test the consequences of reduced HBP1 levels, we used RNA interference to knock down HBP1 and observed increased Wnt signaling, tumorigenic proliferation, and invasiveness in cell and animal breast cancer models. Lastly, statistical analysis of a breast cancer patient database linked reduced HBP1 expression to breast cancer recurrence. In considering two-gene criteria for relapse potential, reduced expression of HBP1 and SFRP1, which is another Wnt inhibitor that was recently linked to invasive breast cancer, strikingly correlated with recurrence. Together, these data indicate that HBP1 may be a molecularly and clinically relevant regulator of breast cancer transitions that eventually lead to poor prognosis. [Cancer Res 2007;67(13):6136-45]

Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

“…As shown in Figure 3b, HBP1 is a member of the sequence-specific HMG box family of transcriptional factors with a central repression domain (amino acids 191-400) and a C-terminal HMG box DNA-bindingdomain (amino acids 431-509), as well as retinoblastoma and p38 MAPK-binding regulatory regions Swanson et al, 2004;Paulson et al, 2007). Relevant mutants from our previous work are shown in Figure 3b.…”

“…pmHMG carries a triple-point mutation in the HMG box DNA-binding domain that abolishes DNA binding. The delEx7 mutant was isolated in our breast cancer study and represents a naturally occurring mutant of HBP1 that is associated with invasive breast cancer (Paulson et al, 2007). The exon-skipping deletion in delEx7 creates a premature termination signal, resulting in the deletion of the DNA-binding domain and much of the repression domain.…”

“…Most of our previous works focused on its transcriptional repression and regarded HBP1 as a novel transcriptional repressor in differentiation (Tevosian et al, 1997;Shih et al, 1998Shih et al, , 2001Lemercier et al, 2000;Xiu et al, 2003;Smith et al, 2004;Paulson et al, 2007). Only few studies have reported that HBP1 is a transcriptional activator in myeloid differentiation and transformation (Lavender et al, 1997;Yao et al, 2005).…”

“…We have previously reported that decreased HBP1 and increased WIP1 (a p38 MAPK phosphatase expected to regulate p38MAPK activity in senescence) predict a poor prognosis in breast cancer . Indeed, decreases in HBP1 are associated with a poor prognosis in breast cancer (Paulson et al, 2007). These later cancer-associated changes will be initiated by a loss of senescence that is triggered by the reduction in the HBP1 protein, of which the regulation of the p16 INK4A gene is a central factor.…”

Macrophage migration inhibitory factor is a direct target of HBP1-mediated transcriptional repression that is overexpressed in prostate cancer

“…The vectors were a kind gift from Dr Amy S Yee. The knockdown experiment was performed as described previously (Paulson et al, 2007). The HBP1 shRNA target sequence is ACTGTGAGTGCCACTTCTC.…”