Ras stimulation of E2F activity and a consequent E2F regulation of integrin alpha6beta4 promote the invasion of breast carcinoma cells.
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.
Yoon
Sang-Oh
SO
Division of Cancer Biology and Angiogenesis, Department of Pathology Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Shin
Sejeong
S
Mercurio
Arthur M
AM
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D003094:Collagen; D004338:Drug Combinations; D050684:E2F Transcription Factors / Q000378:metabolism*; D006801:Humans; D039161:Integrin alpha6beta4 / Q000096:biosynthesis* / Q000235:genetics; D007797:Laminin / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D011509:Proteoglycans; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D004338:Drug Combinations; D050684:E2F Transcription Factors; D039161:Integrin alpha6beta4; D007797:Laminin; D011509:Proteoglycans; D012333:RNA, Messenger; C059485:matrigel; D003094:Collagen; D018631:ras Proteins