Research Grants Awarded
Epidermal growth factor receptor (EGFR)-related protein (ERRP), a novel pan-erbB inhibitor, is a potential targeted therapy for breast cancer.
Tumor Cell Biology V
Background: Epidermal growth factor receptor (EGFR) pathway is frequently dysregulated in human breast cancer (HBC). Therefore, inactivation of EGFRs (EGFR, HER-2, HER-3, and HER-4) is a promising strategy for the development of selective therapies against breast cancer. Current anti-EGFR therapies such as cetuximab (ErbituxR), gefitinib (IressaR) or trastuzumab (HerceptinR) target EGFR or HER-2 but not both. Since HBCs often express different EGFRs, identification of inhibitor(s) that target multiple EGFRs may provide a therapeutic benefit to a broader patient population. In this context, a natural pan-erbB inhibitor called ERRP (EGFR-Related Protein) was recently identified and characterized. ERRP, a ~55 kDa protein, is present in most, if not all, normal human epithelial cells. Growth of HBC cells that over express EGFR and HER-2 was inhibited by ERRP in a dose-dependent manner. ERRP inhibited TGF-alpha or heparin-binding EGF (HB-EGF)-induced activation of EGFR and HER-2. ERRP also stimulated apoptosis in HBC cells (Mol. Cancer Ther. 3: 1615-1621, 2004). In contrast, ERRP did not inhibit growth of mouse fibroblast (NIH-3T3) cells. Although the mechanisms of ERRP inhibition of EGFRs are not fully known, our data suggest that ERRP competes with EGFR for the ligand(s) and likely forms inactive heterodimers with the EGFR thereby interfering with the EGFR signal transduction processes. Objective/ Hypothesis: Since ERRP is a pan-erbB inhibitor, we hypothesize that ERRP is a superior inhibitor of the growth of breast cancers that express varying levels of EGFRs. Here we will study effectiveness of ERRP in inhibiting the growth of HBC cell-derived tumor xenografts, in vivo. Specific Aims: 1.To compare effectiveness of ERRP alone and in combination with cetuximab and trastuzumab. 2.To compare regulation of ERRP-dependent inhibition of tumor growth with that of cetuximab or trastuzumab. 3.To determine whether expression of constitutively active MEK2 and/or p21Rac1 will inhibit tumor suppression by ERRP. Study Design: Affinity purified ERRP will be utilized in proposed studies. In aim 1, HBC cell xenografts will be grown as subcutaneous tumors in SCID mice, and a comparison of their growth inhibition by ERRP, trastuzumab, or cetuximab will be carried out. In aim 2, we will compare effects of ERRP with cetuximab and trastuzumab on proliferation and apoptosis, on activation of EGFR and/or HER-2, tissue distribution of ERRP, and sequestration of EGFR ligand(s) by ERRP. Aim 3 we will study whether HBC cell-derived tumors expressing activated MEK2 or p21Rac1show diminished growth inhibition by ERRP. Potential Outcomes: Activated EGFR and/or HER-2 are often noted in breast cancer, and play a role in breast cancer progression. Blocking of EGFR/HER-2 activity and their signaling pathways is an effective therapeutic approach. ERRP, naturally occurring pan-erbB inhibitor, is likely to provide a therapeutic benefit to a broad range of patient population.
Breast cancer is the most common cancer among women. It is the second leading cause of cancer death in women, after lung cancer. One in seven women will get breast cancer at some point in their lives. About 211,240 women in the United States will be diagnosed with invasive breast cancer in 2005 and about 20% of the women diagnosed with breast cancer will die from this disease. Breast cancer death rates declined significantly from 1992 to 1996, with the largest decrease in younger women-- both white and black. This decline is probably the result of earlier detection and improved treatment. The established therapy regimen for breast cancer involves surgery, frequently augmented by radiation and/or chemotherapy. Limitations of the existing approach include toxic side effects of radiation and chemotherapy as well as less than fully successful outcomes. Development and progression of breast cancer are influenced by multiple factors. Several critical genes including estrogen receptor (ER), progesterone receptor (PR), retinoic acid receptor (RAR)-beta, epidermal growth factor receptor (EGFR) family members (EGFR, HER-2, HER-3, and HER-4), and tumor suppressor p53 are known risk factors for development of disease, predictors of prognosis and response to therapy, and serve as therapeutic targets. EGFR pathway is frequently hyperactivated or dysregulated in human breast carcinoma (HBC) involving range of mechanisms, including overproduction of ligands, overproduction of the receptor, and/or constitutive activation of the receptor. Recently, a natural inhibitor of EGFRs called ERRP (EGFR-Related Protein) was identified and characterized. ERRP is present in most, if not all, normal human epithelial cells. Growth of estrogen-receptor alpha negative human breast cancer (HBC) cells, that express high levels of EGFR (MDA-MB-468) and HER-2 (SKBR-3), was inhibited by ERRP. Treatments with ERRP also stimulated HBC cell death (apoptosis). In contrast, ERRP caused no inhibition of growth of normal mouse fibroblast cells. We hypothesize that ERRP is a superior inhibitor of human breast cancers, when compared with Cetuximab (that predominantly targets EGFR-over expressing tumors) or Trastuzumab (that predominantly targets HER-2-over expressing tumors), and may be of therapeutic value to a broader patient population. This study is a step towards establishing ERRP as an anti-breast cancer therapeutic. The objective of this investigation is to (a) compare the effectiveness of ERRP with cetuximab and trastuzumab in inhibiting the growth of tumors in immune deficient SCID mice produced by EGFR as well as Her-2 over expressing HBC cells, and (b) the mechanisms by which ERRP exerts its anti-tumor effects.