The roles of epigenetic alterations in HER2-mediated breast tumorigenesis

The HER2 oncogene is overexpressed in approximately 20-30% of all breast cancers. Overexpression of HER2 gene is associated with a shortened disease-free interval, aggressive metastatic features and poor survival. Although HER2-targeting therapeutic agents, such as trastuzumab and lapatinib, have been developed for therapy of HER2-positive breast cancers, a significant portion of patients fail to respond to these anti-cancer agents and a majority of initial responders have a relapse within several years. Therefore, the development of effective therapeutic strategies for treating these de novo and acquired trastuzumab-resistant HER2-positive breast tumors is still highly warranted. In addition to therapeutic development, identification of critical molecules as targets for development of prospective chemopreventive agents and early detection approaches for HER2-type breast cancer would be another more promising direction to cure this HER2-type breast cancer.

Development of cancer has been known to involve both genetic alterations in DNA as well as epigenetic changes in DNA and chromatin. During tumorigenesis, abnormalities in cellular epigenetics lead to global genomic hypomethylation that gives rise to genomic DNA instability and inducible expression of oncogenes, and local promoter hypermethylation that cooperates with histone modifications to silence tumor suppressor genes. Collaboration between genetic and epigenetic alterations leads to pathological changes in cellular signal transduction and gene expression, which triggers cell transformation into cancer stem cells (CSCs) and promotes tumorigenic and metastatic progression. For the connection between HER2-positive breast cancer and epigenetics, it has been shown that HER2-type breast cancers exhibit more frequent CpG island hypermethylation of tumor suppressor genes, suggesting that epigenetic alterations play a crucial role in HER2-induced development of mammary CSCs and tumorigenesis. In our research, we explore the roles of epigenetic alterations in HER2-mediated breast cell transformation into CSCs which develop breast tumorigenesis and their therapeutic as well as chemopreventive implications.

The role of forkhead box-F1 transcription factor in tumorigenesis

Forkhead box (FOX) proteins are an evolutionarily conserved, ancient gene family that was discovered after the identification of the Drosophila melanogaster gene fork head (fkh). FOX proteins function as transcription factors with the evolutionarily conserved DNA-binding domain termed forkhead box or the winged helix domain. Many members of the FOX gene family have been documented to play pivotal roles in embryonic development and also in the control of a variety of physiological processes, such as cell cycle progression, cell survival, cellular metabolism, life span, and immune responses.

The human FOXF1 gene encodes a homologue of the mouse forkhead box-F1 (Foxf1) transcription factor. Gene knockout studies have shown that the mouse Foxf1 takes an indispensable role of a regulator in organ morphogenesis, including the lung, liver, gallbladder, esophagus, and trachea. Although the roles of Foxf1 in mouse development have been extensively documented, the biochemical roles of its functions in mammalian cells are largely unknown. We recently discovered that human FOXF1 plays a novel tumor-suppressor role in cell-cycle regulation of mammary epithelial cells, which is frequently silenced in breast cancer through epigenetic mechanisms. In addition to the relevance of FOXF1 in breast cancer, we recently have revealed that FOXF1 expression is predominantly silenced in colorectal cancer cell lines with the inactive p53 gene. By using wild-type, p53-null and p21WAF1-null HCT116 colorectal cancer cell line models, we have demonstrated that knockdown of FOXF1 by siRNA led to DNA over-replication (a mechanism causing genomic instability) in colorectal cancer cells with a defect in the p53-p21WAF1 checkpoint. Intriguingly, our most recent studies have revealed that the FOXF1 protein is overexpressed as well as mislocalized in cancerous epithelial cells and underexpressed/lost in tumor-associated stromal fibroblasts of colorectal adenocarcinomas, and suggest that FOXF1 is a potential prognostic marker due to its association with the malignancy and metastasis of colorectal cancer. Given the potential role of FOXF1 in breast and colorectal tumorigenesis, our research is aimed at elucidating the functions of FOXF1 in cells, in particular its downstream target genes, and revealing the regulation of expression, subcellular localization and post-translational modifications of FOXF1 in cancers.