Inhibitors of differentiation or DNA binding (Id) proteins have been shown to be 
involved in tumor growth, invasiveness, metastasis, and angiogenesis. 
Overexpression of Id proteins, especially Id1, correlates with unfavorable 
clinical prognosis. Thus, they are attractive molecular targets for anticancer 
therapy. Overexpression of Id proteins mediates breast cancer metastasis to 
lung. Targeting Id1 and Id3 expression in breast cancer cells reduces breast 
cancer metastasis in animal models. Different breast tumors failed to grow 
and/or metastasize in Id1 (+/-) Id3 (-/-) mice. Id1 and Id3 preferentially 
dimerize with the key regulatory E-proteins which inhibit the expression of 
different tumor suppressor genes. Nevertheless, the inhibition of tumorigenic 
activities of Id1 and Id3 at protein level has never been studied. Here, we 
isolated a novel peptide aptamer, Id1/3-PA7, specifically interacting with Id1 
and Id3 from randomized combinatorial expression library using yeast and 
mammalian two-hybrid systems. Intracellular delivered Id1/3-PA7 co-localized to 
Id1 and Id3 and interfered with their functions. It repressed E47 protein 
sequestration by Id1 and Id3, activated the E-box promoter and increased the 
expression level of cyclin-dependent kinase inhibitors (CDKN1A and CDKN1B) in a 
dose-dependent fashion, paralleled by the cleavage of poly ADP ribose polymerase 
(PARP). These effects were counteracted by ectopically overexpressed Id1 and 
Id3. Peptide aptamer Id1/3-PA7 induced cell cycle arrest and apoptosis in breast 
cancer cells MCF7 and MDA-MB-231. In conclusion, Id1/3-PA7 could represent a 
nontoxic exogenous agent that can significantly provoke antiproliferative and 
apoptotic effects in breast cancer cells, which are associated with deregulated 
expression of Id1 and Id3.