The Role Of ITGBL1and Its Transcription Regulation Mechanism In Breast Cancer Metastasis

Backgorund:Integrins are important adhesion receptors that mediate the adhesive functions of many cell types,enabling cells to interact with one another and with the extracellular matrix(ECM). Integrins are a superfaminly of dimerci αβ cell-surface glycoproteins, contain large extracellular domain, a short transmembrane domain and intracellular domain, and extracellular domain is composed of a globular headpiece and stalk region connectting the ligand-binding headpiece to the transmembrane and cytoplasmic domains. All eight identified integrin β subunits are highly similar, where the stalk region is composed of a fourfold repeat of a cysteine-rich segment that is thought to be homologous to the laminin-epidermal growth factor(EGF) modules, a special type of EGF domain with eight cysteines. EGF-like domain contains in many growth factors receptor, adhesion molecules, and proteins of the coagulation and fibrinnolytic pathway have either been shown or are expected to participate in protein-protein or protein-cell interactions.Integrin beta-like1(ITGBL1) was found in an homolohy search of a human EST cDNA database, using the known amino acid sequences of integrin subunits in1999, encode a sequence comprising a typical signal peptide, followed by a hydrophilic471-amino-acid domain containing10tandem EGF-like repeats strkingly similar to those found in the cysteine rich "stalk-like" structure of integrin β subunits, and the amino acid sequence identity between the TIED and integrin cysteine-rich repeats is as high as68%and is highly statistically significant, implying that the TIED and integrin cysteine-rich repeats have the same protein fold. ITGBL1may be connection protein between hematopoietic progenitor cells and mesenchymal stem cell, which is conducive to the stability of hematopoietic progenitor cells. Using cDNA microarray analysis, we have found that ITGBL1mRNA level is down-regulated in breast cancer lymph node metastasis compared to the primary tumor, which suggested that it may be a potential metastasis-related gene of breast cancer. However, the biological function and the role of ITGBL1in carcinogenesis and development of cancer was unknown.Objective:The purpose of this study was to clarify the relationships between ITGBL1mRNA level and clinicopathological factors in breast cancer, and to evaluate its clinincal value in predicting the prognosis of breast cancer patients. To identify the region in ITGBL1gene promotor where the transcriptional factor Runx2can bind.Methods:Real-time reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the mRNA expression level of ITGBLl in primary invasive ductal carcinoma of180cases.Transcription factors that can associated with the promotor region of ITGBL1gene were predicted by biological information software and then validated by using Chromatin immunoprecipitation (CHIP) and PCR technique.Results:The expression levels of ITGBL1in ER-negative breast cancer were lower than that of ER-positive(P=0.006), in histological grade III were lower than that of histological grade Ⅰ-Ⅱ(P=0.036), in clinincal stage III were lower than that of clinical stage I-II(P=0.060), while no statistically significant difference was observed between two groups with regard to different age, menostasis status, tumor size, lymph node status and status of PR and Her2. Three years disease-free survival and metastasis-free survival of cases with low ITGBL1were lower than cases with high ITGBL1(P=0.068, P=0.033), while five years disease-free survival and metastasis-free survival between these two groups were not significantly different but showed the same trend with that of three years.Conclusion:High ITGBL1mRNA level is one of the biological characteristics of ER-positive breast cancer. The under-expressed ITGBL1mRNA is associated with poor differentiation, tumor progression and poor prognosis, and it is a potential molecular marker for predicting prognosis of breast cancer patients.Runx2may be an important transcriptional factor which regulates COL11A1gene.