Title

Ras stimulation of E2F activity and a consequent E2F regulation of integrin alpha6beta4 promote the invasion of breast carcinoma cells

UMMS Affiliation

Department of Cancer Biology

Date

6-17-2006

Document Type

Article

Subjects

Animals; Breast Neoplasms; Cell Adhesion; Cell Line, Tumor; Collagen; Drug Combinations; E2F Transcription Factors; Humans; Integrin alpha6beta4; Laminin; Mice; NIH 3T3 Cells; Neoplasm Invasiveness; Proteoglycans; RNA, Messenger; Transfection; ras Proteins

Abstract

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 beta4 integrin subunit, a component of the alpha6beta4 integrin that is known to enhance carcinoma invasion. Specifically, expression of E2Fs1-3 increased beta4 mRNA, protein, and cell surface expression. The active E2Fs were unable to stimulate invasion in cells that expressed a beta4 short hairpin RNA. This effect of the active E2Fs on beta4 expression does not seem to result from E2F-mediated beta4 transcription because the beta4 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 alpha6beta4 integrin in a common pathway that culminates in enhanced alpha6beta4-dependent invasion.

Rights and Permissions

Citation: Cancer Res. 2006 Jun 15;66(12):6288-95. Link to article on publisher's site

Related Resources

Link to Article in PubMed

PubMed ID

16778205