| Kruppel-like factor 4 (KLF4) is a zinc-finger transcription factor which plays an integral role in a myriad of cellular processes, ranging from regulation of the cell cycle in modulating proliferation and apoptosis, to exquisite control of differentiation and cell morphology during both development and normal tissue homeostasis, as well as disease progression. The advent of induced pluripotent stem (iPS) cell generation has expanded KLF4's regulatory repertoire to include a functional role in the maintenance and renewal of the stem cell state. Initially discovered in a genetic screen to identify transcription factors involved in growth regulation, KLF4 was first described as gut-enriched Kruppel-like factor (GKLF) and epithelial zinc finger (EZF), as expression was found to be enriched in epithelial versus mesenchymal cells, and those of the gastrointestinal tract. Subsequent studies have identified diverse regulatory roles for KLF4 in a multitude of cell types and tissues, from the cornea to the cardiovascular system.;The role of KLF4 during diseased states is as diverse as its function during normal development and tissue homeostasis. Predominantly recognized as an anti-proliferative factor, the first implications of its role as a tumor suppressor came from studies demonstrating loss of KLF4 in gastric and colorectal cancers. However, evidence of increased KLF4 expression in squamous cell carcinoma and ductal carcinoma of the breast suggested an additional and opposing oncogenic function for this transcription factor.;To determine the functional role of KLF4 in breast cancer, we first sought to better understand its role in normal mammary epithelial cell biology. Using the non-transformed MCF-10A mammary epithelial cell line, we found that loss of KLF4 resulted in the conversion of these cells from a cuboidal, epithelial morphology to an elongated, fibroblastic phenotype. Additionally, molecular alterations, such as loss of E-cadherin, coupled with increased migration were suggestive of an epithelial-to-mesenchymal transition (EMT). Conversely, overexpression in a highly metastatic tumor line was able to reduce their migratory and invasive capacity, suggesting an inhibitory role for KLF4 in the regulating the metastatic potential of breast cancer cells.;Using two independent mouse models of mammary gland tumorigenesis, we were able to demonstrate that KLF4 expression is lost in HER2/Neu -induced mammary tumors, while overexpression of KLF4 in an orthotopic 4T1 tumor model reduced primary tumor growth as well as inhibited distant metastases. These data lead us to conclude that KLF4 functions as tumor and metastasis suppressor in the breast. |
