Breast cancer growth inhibition by delivery of the MDGI-derived peptide P108

Abstract

Mammary derived growth inhibitor (MDGI) is a member of the family of cytoplasmic fatty acid binding proteins (FABPs), which bind hydrophobic ligands such as fatty acids, retinoids, eicosanoids and prostaglandines. MDGI and an 11 amino acid MDGI-derived conserved Cterminal peptide (P108) inhibits growth of normal mammary epithelial cells in tissue and organ culture, but fails to inhibit proliferation of many breast cancer cell lines in vitro. Here, the e ects of peptide P108 on tumor growth of MCF-7, MDA-MB468 and MDA-MB231 human breast cancer cell lines in nude mice were tested. To deliver P108 into tumors, a novel peptide production system was applied for expression and secretion of small bioactive peptides in mammalian cells. Functional di erentiation was observed in MCF-7 and MDA-MB468 cells upon P108 expression. In addition, EGF-dependent colony formation in soft agar by MDA-MB468 cells was inhibited by secreted P108. Tumor growth in athymic nude mice was suppressed in all three cell lines tested. Furthermore, P108 expressed by MCF-7/P108 cells caused paracrine tumor growth inhibition of MDA-MB231 cells. These results indicate that breast cancer inhibition by P108 is independent of binding to hydrophobic ligands and is perhaps mediated by interference with EGF-dependent signaling pathways.

Structural and functional analysis of fatty acid-binding proteins

“…It has been proposed that the structural element responsible for these HFABP effects is the C-terminal undecapeptide of the protein. When expressed in breast cancer cell lines, this 11-residue peptide, which comprises the b-J strand of HFABP, reduced colony formation in vitro and tumor growth in inoculated nude mice (34). This implies that such effects of HFABP may be entirely independent of their FA ligand.…”

Gene Expression Profiles of Primary Breast Carcinomas from Patients at High Risk for Local Recurrence after Breast-Conserving Therapy

“…In vitro studies have shown that FABP3 inhibits growth of normal mammary epithelial cells (39,40) and that it is highly expressed in terminally differentiated mammary cells in contrast to proliferating tissue from pregnant animals (41,42). However, FABP3 fails to inhibit proliferation of some breast cancer cell lines (43,44).…”

Mammary-derived growth inhibitor (MDGI) interacts with integrin α-subunits and suppresses integrin activity and invasion

“…Here, we show that expression of MDGI correlates with reduced b1-integrin activity and invasion in vitro and with increased DDFS in breast cancer patients. We propose that MDGIinduced inhibition of b1-integrin function is linked to the putative tumor-suppressor functions assigned to MDGI in earlier studies (Wang and Kurtz, 2000). Hypermethylation has been shown to result in silencing of MDGI expression in breast cancer (Huynh et al, 1996), thus it is possible that loss of MDGI and increased integrin activity are the result of epigenetic changes occurring during cancer progression.…”

“…Some FABP functions may be independent of their fatty acid ligand. A C-terminal-derived 11 amino acids peptide of MDGI reduced colony formation of breast cancer cell lines in vitro and tumor formation in nude mice (Wang and Kurtz, 2000). However, MDGI lacks an N-terminal signal peptide and it is not clear whether it or its fragments are secreted in vivo (Clark et al, 2000).…”