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Ras Stimulation of E2F Activity and a Consequent E2F Regulation of Integrin ₆ß₄ Promote the Invasion of Breast Carcinoma Cells

Division of Cancer Biology and Angiogenesis, Department of Pathology Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

Requests for reprints: Arthur M. Mercurio, Department of Cancer Biology, University of Massachusetts Medical School, LRB-408, 364 Plantation Street, Worcester, MA 01605. Phone: 508-856-8676; Fax: 508-856-1310; E-mail: arthur.mercurio{at}umassmed.edu.

Active Ras proteins contribute to breast carcinogenesis and progression. Here, we provide evidence that active H-Ras regulates the expression and activity of the E2F family of transcription factors in SUM-159 breast carcinoma cells. In addition, we show by using a DNA-binding mutant of E2F, as well as expression of specific E2Fs that are transcriptionally active, that the active E2Fs1-3 can mediate the H-Ras-dependent invasion of SUM-159 cells. The inhibitory E2Fs4-5, in contrast, do not influence invasion. One mechanism by which the active E2Fs promote H-Ras-dependent invasion seems to be their ability to increase expression of the ß₄ integrin subunit, a component of the ₆ß₄ integrin that is known to enhance carcinoma invasion. Specifically, expression of E2Fs1-3 increased ß₄ mRNA, protein, and cell surface expression. The active E2Fs were unable to stimulate invasion in cells that expressed a ß₄ short hairpin RNA. This effect of the active E2Fs on ß₄ expression does not seem to result from E2F-mediated ß₄ transcription because the ß₄ promoter lacks known E2F binding motifs. In summary, the data reported here indicate a novel mechanism by which H-Ras can promote the invasion of breast carcinoma cells. This mechanism links active H-Ras, transcriptionally active E2F, and the ₆ß₄ integrin in a common pathway that culminates in enhanced ₆ß₄-dependent invasion. (Cancer Res 2006; 66(12): 6288-95)

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