Abstract
BackgroundThe Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in up to 70 % of sporadic breast cancers depending on subtype; however, the effects of APC mutation on tumorigenic properties remain unexplored. Using the ApcMin/+ mouse crossed to the Polyoma middle T antigen (PyMT) transgenic model, we identified enhanced breast tumorigenesis and alterations in genes critical in therapeutic resistance 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. Mechanistic studies in tumor-derived cell lines demonstrated that focal adhesion kinase (FAK)/Src/JNK signaling regulated the enhanced proliferation downstream of Apc mutation. Despite this mechanistic information, the role of APC in mediating breast cancer chemotherapeutic resistance is currently unknown.MethodsWe have examined the effect of Apc loss in MMTV-PyMT mouse breast cancer cells on gene expression changes of ATP-binding cassette transporters and immunofluorescence to determine proliferative and apoptotic response of cells to cisplatin, doxorubicin and paclitaxel. Furthermore we determined the added effect of Src or JNK inhibition by PP2 and SP600125, respectively, on chemotherapeutic response. We also used the Aldefluor assay to measure the population of tumor initiating cells. Lastly, we measured the apoptotic and proliferative response to APC knockdown in MDA-MB-157 human breast cancer cells after chemotherapeutic treatment.ResultsCells obtained from MMTV-PyMT;ApcMin/+ tumors express increased MDR1 (multidrug resistance protein 1), which is augmented by treatment with paclitaxel or doxorubicin. Furthermore MMTV-PyMT;ApcMin/+ cells are more resistant to cisplatin and doxorubicin-induced apoptosis, and show a larger population of ALDH positive cells. In the human metaplastic breast cancer cell line MDA-MB-157, APC knockdown led to paclitaxel and cisplatin resistance.ConclusionsAPC loss-of-function significantly increases resistance to cisplatin-mediated apoptosis in both MDA-MB-157 and the PyMT derived cells. We also demonstrated that cisplatin in combination with PP2 or SP600125 could be clinically beneficial, as inhibition of Src or JNK in an APC-mutant breast cancer patient may alleviate the resistance induced by mutant APC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1456-x) contains supplementary material, which is available to authorized users.
Highlights
The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in up to 70 % of sporadic breast cancers depending on subtype; the effects of APC mutation on tumorigenic properties remain unexplored
Understanding how APC mediates sensitivity of breast tumor cells to chemotherapy is crucial to future breast cancer treatment, as the tumors that arise in Apc-mutant MMTV-Polyoma middle T antigen (PyMT) mice resemble human metaplastic breast cancer, an aggressive subtype of triple-negative breast cancer (TNBC) with limited targeted therapies
MMTVPyMT;Apc+/+ have a greater expression of ABCG2 protein compared to MMTV-PyMT;ApcMin/+ cells (Fig. 1d and f, Additional file 1)
Summary
The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in up to 70 % of sporadic breast cancers depending on subtype; the effects of APC mutation on tumorigenic properties remain unexplored. Mechanistic studies in tumor-derived cell lines demonstrated that focal adhesion kinase (FAK)/Src/JNK signaling regulated the enhanced proliferation downstream of Apc mutation. Despite this mechanistic information, the role of APC in mediating breast cancer chemotherapeutic resistance is currently unknown. The Adenomatous Polyposis Coli (by convention, the human and mouse genes are APC and Apc, respectively, whereas the protein from all species is APC) tumor suppressor is mutated or silenced by hypermethylation in up to 70 % of sporadic breast cancers depending on subtype ([7, 8] reviewed in [9]). Understanding how APC mediates sensitivity of breast tumor cells to chemotherapy is crucial to future breast cancer treatment, as the tumors that arise in Apc-mutant MMTV-PyMT mice resemble human metaplastic breast cancer, an aggressive subtype of triple-negative breast cancer (TNBC) with limited targeted therapies
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