Mammaglobin-Based Strategies for Treatment of Breast Cancer

Peter   S.   Goedegebuure; Mark   A.   Watson; Carsten   T.   Viehl; Timothy   P.   Fleming

Abstract

Mammaglobin is a gene that is expressed almost exclusively in the normal breast epithelium and human breast cancer. It is a member of the secretoglobin gene family and forms a heterodimer with lipophilin B. We have focused on the tissue-specificity of mammaglobin as a potential mechanism for the specific killing of breast cancer cells. By elucidating the promoter region of mammaglobin, we hope to utilize this site as a method for turning on the apoptosis inducer gene, Bax, in breast cancer cells. The Bax gene will only be expressed at levels necessary to induce apoptosis in mammaglobin positive cells. This would include > 80% of all breast cancer cells and some normal breast epithelium. This type of targeted killing could be conceptualized as a biochemical mastectomy; that is, genetic ablation of breast tumor cells and perhaps non-malignant breast epithelium while preserving the adipose and stromal components of the breast. Work is also being done to address the binding specificity of the secreted mammaglobin protein. There is early evidence that the mammaglobin heterodimer may in fact bind to breast and breast cancer cells. If this finding is validated, this creates the possibility that mammaglobin can be tagged with a radioisotope or a toxin, so that binding of the tagged-mammaglobin complex results in the specific killing of that breast cancer cell. Finally, mammaglobin is being explored as a target for immune-based interventions. In vitro studies have demonstrated that T cellmediated immune responses can be induced against mammaglobin-derived peptides expressed by MHC molecules on tumor cells and antigen-presenting cells. In summary, mammaglobin displays several unique features that make it a promising target for intervention.

Keywords: mammaglobin, breast cancer, diagnosis, therapy, apoptosis, antibody, t lymphocyte, vaccine