The triple negative breast cancer (TNBC) is an aggressive form of breast cancer frequently seen in African American women and BRCA1 mutation carriers. The TNBC tumors often relapse with distant metastases following standard cytotoxic chemotherapy. The overarching research objective of this small research application is to elucidate a new mechanism of chemosensitivity of breast cancer. While some apoptotic molecules do enhance cytotoxic effects of chemotherapeutic drugs, to date none of these molecules is a clinically robust target in advanced breast cancer. To this end, we have demonstrated that BLID, BH-3 Like motif containing Inducer of cell Death, is a strong prognostic factor in invasive breast cancer. Recently, BLID expression has been shown to inhibit breast cancer cell growth and metastasis. In addition, BLID mRNA expression is significantly reduced in certain grade 3 relative to grade 1 and grade 2 breast cancers, suggesting a potential role of transcriptional regulation of BLID in breast cancer progression. Despite the fact that members of the Forkhead boxO (FOXO) subfamily of transcriptional regulators have been linked with breast pathogenesis and prognosis, their mechanisms of action in breast cancer are largely unknown. Therefore, approaches that explain and target such mechanisms could offer important clues to safe and effective ways of managing breast cancer. In preliminary studies, BLID seems to be a likely effector of FOXO3a, and expression of BLID cDNA nanotherapeutic increases chemosensitivity in breast cancer cells. Furthermore, microRNAs miR-21, miR-155 and miR-34a may be components of the FOXO/BLID signaling pathway. The specific research aims are: 1) To demonstrate a novel FOXO-BLID signaling pathway and BLID-mediated chemosensitivity in breast cancer cells using DNA affinity purification and mass spectrometry, and the ChIP-Seq strategy. 2) To examine the integrative roles of BLID and microRNAs in chemosensitization of TNBC cells. Successful outcomes of this research will provide the basis for future studies of a comprehensive analysis of the FOXO-BLID signaling pathway that may explain why certain breast cancers fail chemotherapies. This work will also establish the first functional link between BLID and three prominent microRNAs, and may lead to a prospective validation of the microRNA module(s) in clinical TNBC specimens. Building on this project, a new systems biology approach involving FOXO/BLID-centric gene networks and circulating microRNAs could be developed. This information will be unique and significant since very little is known about the systems biology of TNBC cell death and drug sensitivity or resistance.
This research project will offer a strong rationale for detailed studies of the FOXO-BLID signaling pathway in future that may explain why certain breast cancers fail chemotherapies. Together with the microRNA(s) identified in this research, this knowledge may ultimately improve management of a subset of metastatic disease, replacing dose dense polychemotherapy, eliminating toxicity, and resulting in significant reduction in mortality of many breast cancer patients.