KLF4α stimulates breast cancer cell proliferation by acting as a KLF4 antagonist

Kruppel-like factor 4 (KLF4), a transcription factor involved in both tumor suppression and oncogenesis in various human tumors, is subject to alternative splicing that produces KLF4 alpha. KLF4 alpha is primarily expressed in the cytoplasm because it lacks exon 3 of KLF4, which contains the nuclear localization signal. The role of KLF4 in breast cancer remains unclear and nothing is known yet about the expression and function of the isoform KLF4 alpha. Here, we show that KLF4 alpha is expressed in normal and tumoral tissue of the breast and provide evidence that the KLF4 alpha/KLF4(full-length) (FL) ratio is increased in tumors compared to corresponding normal tissue. Forced increase of the KLF4 alpha/KLF4(FL) ratio in the metastatic breast cancer cell line MDA-MB-231 decreases the levels of E-Cadherin, p21(Cip1), and p27(Kip1), three known KLF4(FL) target genes, and stimulates cell proliferation. We suggest that cytoplasmic KLF4 alpha binds to KLF4(FL) and retains it in the cytoplasm thereby antagonizing the gene regulatory activities of KLF4(FL) in the nucleus. Our results establish KLF4 alpha as a KLF4 isoform that opposes the function of KLF4(FL) and as an important factor in the complex and unresolved role of KLF4(FL) in breast carcinogenesis.