p53 and HER2/neu: Breast tumor markers and targets for cancer therapy

As tumor markers, p53 autoantibodies and HER2/neu extracellular domain (ECD) protein may identify women at risk for occurrence and progression of breast cancer. Women with elevated levels may be potential candidates for directed experimental therapeutics. At the time of sample analysis, it was believed that 1,079 subjects chosen from the Long Island Breast Cancer Study Project had blood collected prior to surgery and/or treatment. It was later discovered that only 7% of cases (n = 16 in situs, n = 32 invasives) and 92% of controls (n = 398) did not receive surgery (lumpectomy, mastectomy, and/or cosmetic surgery) and/or treatment (radiation, hormonal and/or chemotherapy); therefore, these subjects were studied. Multivariate linear regression showed that HER2/neu ECD protein was significantly associated with disease status (p = 0.011) and menopausal status (p < 0.001), and was not significantly associated with age (p = 0.669). Chi Square showed that 2.5% of controls, 12.5% of in situ cases and 19% of invasive cases were positive for HER2/neu ECD (p < 0.001). For p53 autoantibodies, univariate linear regression did not produce significant results. Chi Square showed that 2.8% of controls, 6.3% of in situ cases and 6.3% of invasive cases were positive for p53 autoantibodies (p = 0.425).; The use of peptides is widespread in experimental therapeutics; therefore, several p53-derived synthetic peptides were tested for their antiproliferative effects. MDM2-Ant-15 peptide representing the partial MDM2 binding site on p53 and fused to the Drosophila protein Antennapedia was most effective. MDM2-Ant-15 peptide induced necrosis in breast carcinoma cell lines MDA-MB-468, MCF-7 and MDA-MB-157. Much less cytotoxicity was observed in nonmalignant breast epithelial cell line MCF-10-2A. Necrosis was accompanied by loss of p53, MDM2, PARP, Bax, Caspase-3 and α-tubulin. Peptide sensitivity correlated with extent of loss of certain proteins and with level of Caveolin-1 tumor suppressor protein. MDA-MB-468 cells were most sensitive and had low Caveolin-1 levels, whereas MCF-10-2A cells were least sensitive and showed high Caveolin-1 levels. Based on these findings, p53 autoantibodies and HER2/neu ECD protein cannot be recommended as breast tumor markers until further studies, and MDM2-Ant-15 peptide may be a novel peptide therapeutic.