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Artificial Antigen Presenting Cell aAPC Mediated Activation and Expansion of Natural Killer T Cells
Published on: December 29, 2012
APC selectively mediates response to chemotherapeutic agents in breast cancer
Monica K VanKlompenberg1,2, Claire O Bedalov1,3, Katia Fernandez Soto1,3
1Harper Cancer Research Institute, A134 Harper Hall, 1234 Notre Dame Ave., South Bend, IN, 46617, USA.
Background:
The 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.
Methods:
We 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.
Results:
Cells 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.
Conclusions:
APC 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.
Insights
Loss of Adenomatous Polyposis Coli (APC) function in breast cancer increases resistance to chemotherapy. Inhibiting Src or JNK alongside cisplatin may overcome this resistance in APC-mutant tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Adenomatous Polyposis Coli (APC) is a tumor suppressor frequently altered in breast cancer, but its role in tumorigenesis and therapeutic resistance is unclear.
- APC mutations can drive aggressive tumor subtypes, such as metaplastic breast cancer, and influence genes involved in drug resistance.
Purpose of the Study:
- To investigate the impact of APC loss-of-function on breast cancer development and chemoresistance.
- To explore the underlying signaling pathways (e.g., FAK/Src/JNK) and therapeutic strategies for APC-mutant breast cancers.
Main Methods:
- Utilized MMTV-PyMT;ApcMin/+ mouse models and MDA-MB-157 human metaplastic breast cancer cells.
- Assessed gene expression (MDR1), apoptosis, proliferation, and tumor-initiating cells (ALDH assay) following chemotherapeutic treatment (cisplatin, doxorubicin, paclitaxel).
- Investigated the effects of Src (PP2) and JNK (SP600125) inhibition on chemoresistance.
Main Results:
- Apc loss increased multidrug resistance protein 1 (MDR1) expression and conferred resistance to cisplatin and doxorubicin-induced apoptosis in mouse models.
- APC knockdown in human metaplastic breast cancer cells resulted in resistance to paclitaxel and cisplatin.
- APC-mutant cells exhibited an increased population of aldehyde dehydrogenase (ALDH)-positive tumor-initiating cells.
Conclusions:
- Loss of APC function significantly enhances chemoresistance, particularly to cisplatin-mediated apoptosis, in both mouse and human breast cancer models.
- Combined treatment with cisplatin and Src/JNK inhibitors (PP2/SP600125) shows potential clinical benefit for APC-mutant breast cancer patients by overcoming resistance.
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