Abstract 1986: The role of APC in chemotherapeutic responsiveness of breast cancer
Authors: Soto Katia Fernandez , VanKlompenberg Monica K. , Prosperi Jenifer R. 
Published: May 2015

Breast cancer is the leading cause of cancer-related death in non-smoking women. Despite tremendous amounts of information about the etiology of breast cancer, many questions remain unanswered. It has been demonstrated that specific subtypes of breast cancer respond differently to chemotherapeutic and targeted therapies. The oncogenic events and signaling pathways driving these tumor subtypes are distinct, indicating that increased knowledge of their molecular basis will provide opportunities for novel therapeutic approaches and knowledge of therapeutic responsiveness, to ultimately improve patient outcomes. The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in 18-70% of sporadic breast cancers depending on subtype; however, the effect of APC mutation on tumorigenic properties remains unexplored. APC binds both directly and indirectly to microtubules and regulates multiple components of the DNA repair pathway, suggesting it may play a critical role in therapeutic responsiveness. Using the ApcMin/+ mouse model, we previously identified pre-neoplastic lesions in the breast, alterations in genes critical in therapeutic resistance, and enhanced breast tumorigenesis in the presence of the Polyoma middle T antigen (PyMT) oncogene independent of Wnt/β-catenin signaling. Apc mutation changed the tumor histopathology from solid to squamous adenocarcinomas, resembling the highly aggressive human metaplastic breast cancer. Cell lines derived from PyMT-mediated tumors demonstrated alterations in expression of two ATP-binding cassette transporters, multidrug resistance protein 1 (MDR1) and ATP-binding cassette sub-family G member 2/Breast Cancer Resistance Protein (ABCG2/BCRP), both of which are critical in predicting responsiveness to therapeutic agents. Given that one aspect of therapeutic resistance is an increase in tumor initiating cells (TIC), an ALDEFLUOR assay was performed and surprisingly showed a decrease in TIC population in cells from MMTV-PyMT;ApcMin/+ mice. In addition, cells from MMTV-PyMT;ApcMin/+ mice were more sensitive to paclitaxel and 5-fluorouracil via MTS assay. To translate our findings to a human breast cancer cell line, we utilized DU4475 cells, which harbor a mutation in APC in the β-catenin binding region. We have generated stable DU4475 cell lines expressing the middle region or C-terminal domain of APC, and showed that these cell lines have increased sensitivity to paclitaxel, 5-fluorouracil, cisplatin, and doxorubicin. Combined, these data suggest that APC does modulate therapeutic resistance in breast cancer cells in a context-dependent manner. Future studies will involve the continued studies in the DU4475 cohort of cells and testing the specificity of APC in regulating the therapeutic response in the PyMT-derived cell lines.

Citation Format: Katia Fernandez Soto, Monica K. VanKlompenberg, Jenifer R. Prosperi. The role of APC in chemotherapeutic responsiveness of breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1986. doi:10.1158/1538-7445.AM2014-1986