Induction of autophagy and inhibition of tumorigenesis by beclin 1

The process of autophagy, or bulk degradation of cellular proteins through an autophagosomic-lysosomal pathway(1), is important in normal growth contr ol and may be defective in tumour cells(2) However, little is known about t he genetic mediators of autophagy in mammalian cells or their role in tumou r development. The mammalian gene encoding Beclin 1 (ref. 3), a novel Bcl-2 -interacting, coiled-coil protein, has structural similarity to the yeast a utophagy gene, apg6/vps30 (refs 4, 5), and is mono-allelically deleted in 4 0-75% of sporadic human breast cancers and ovarian cancers(6). Here we show using gene-transfer techniques, that beclin 1 promotes autophagy in autoph agy-defective yeast with a targeted disruption of agp6/vps30, and in human MCF7 breast carcinoma cells. The autophagy-promoting activity of beclin 1 i n MCF7 cells is associated with inhibition of MCF7 cellular proliferation, in vitro clonigenicity and tumorigenesis in nude mice. Furthermore, endogen ous Beclin 1 protein expression is frequently low in human breast epithelia l carcinoma cell lines and tissue, but is expressed ubiquitously at high le vels in normal breast epithelia. Thus, beclin 1 is a mammalian autophagy ge ne that can inhibit tumorigenesis and is expressed at decreased levels in h uman breast carcinoma. These findings suggest that decreased expression of autophagy proteins may contribute to the development or progression of brea st and other human malignancies.