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A Truncated‐Flt1 Isoform of Breast Cancer Cells Is Upregulated by Notch and Downregulated by Retinoic Acid

We have previously reported that the major isoform of Flt1/VEGFR‐1 expressed in MDA‐MB‐231 breast cancer cells was a truncated intracellular isoform transcribed from intron 21 (i21Flt1). This isoform upregulated the active form of Src and increased breast cancer cell invasiveness. Since expression of the transmembrane and soluble Flt1 isoforms of HUVEC is activated by Notch signaling, we wondered whether the expression of the intracellular isoform i21Flt1 was also dependent on Notch activation. We report here that the expression of i21Flt1 in HUVEC and MDA‐MB‐231 cells is downregulated by the γ‐secretase inhibitor DAPT. In addition, treatment of MDA‐MB‐231 cells with siRNA specific for Notch‐1 and Notch‐3 downregulates the expression of i21Flt1. In agreement with these findings, HUVEC and MDA‐MB‐231 breast cancer cells, cultured on dishes coated with recombinant human Dll4 extracellular domain, express higher levels of i21Flt1. In cancer cells, Flt1 is a target of the micro RNA family miR‐200. In MDA‐MB‐231 breast cancer cells, the truncated intracellular isoform i21Flt1 is also negatively regulated by miR‐200c. Retinoic acid interferes i21Flt1 expression by downregulating Notch‐3 and upregulating miR‐200 expression. Treatment of MDA‐MB‐231 breast cancer cells with both a γ‐secretase inhibitor and retinoic acid suppresses the expression of i21Flt1, providing a new mechanism to explain the effectiveness of this therapeutic approach. J. Cell. Biochem. 115: 52–61, 2014. © 2013 Wiley Periodicals, Inc.