Targeting DNA Repair Function of Breast Cancer Stem Cells

Institution: Scripps Research Institute
Investigator(s): Xiaohua Wu, Ph.D. -
Award Cycle: 2009 (Cycle 15) Grant #: 15IB-0051 Award: $284,660
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2009)

Recurrence and treatment-resistant metastasis are the major cause of mortality in breast cancer patients. According to the cancer stem cell theory, a rare breast cancer stem cell population drives tumor growth and metastasis. It is critical to eradicate breast cancer stem cells for successful treatment. Current studies suggest that breast cancer stem cells or tumor initiating cells are more resistant to chemotherapy drugs and radiation by virtue of elevated repair capacity. Therefore, modulation of DNA damage response network to minimize repair function of breast cancer stem cells can potentially sensitize these cells to chemotherapy drugs and radiation.

The unique mechanisms of DNA repair pathways of breast cancer stem cells are unknown. In our first aim, we propose to use our breast cancer stem cell-based model and assay systems to identify targets in the DNA repair pathways that can be used to sensitize breast cancer stem cells to chemotherapy and radiotherapy. For these studies, we will use a high-throughput method adapted for breast cancer stem cells to screen a human RNA interference (RNAi) library and identify targets, which are suitable for drug design and development in the future. Our second aim is to test the effect of histone deacetylase (HDAC) inhibitors in sensitizing breast cancer stem cells to chemotherapy drugs and radiation. For these studies we will evaluate the efficacy of HDAC inhibitors to sensitize breast cancer stem cells to chemotherapy drugs and radiation using both cell-culture and animal models.

Compromising DNA repair ability may be an effective way to reverse the resistance of breast cancer stem cells to chemo- and radiation therapy. If promising HDAC inhibitors are identified, they will be used in new clinical trials for breast cancer treatments. In addition, our proposed high throughput screening and assays can be adapted to other studies to advance breast cancer stem cell research.




Final Report (2010)

Breast cancer continues to be the second leading cause of cancer death in American women. High mortality is mainly due to relapse from therapy-resistant cancer cells. Discovering effective treatment is thus urgent for improving survival rate. Based on substantial evidence, it has been suggested that a rare breast cancer stem (tumor initiating) cell population exists in breast tumors. This population is capable of self-renewing and driving tumor growth and metastasis. It is thus critical to eradicate breast cancer stem cells for successful treatment.

Chemotherapy drugs and radiation kill cancer cells by generating DNA damage and cells die when they fail to repair the damage. We and others found that breast cancer stem cells have higher capability to repair DNA lesions generated by various chemotherapy drugs and radiation, which is one of the major reasons for the resistance to chemotherapy and radiation therapy. We hypothesize that modulation of DNA damage response network to minimize repair function of breast cancer stem cells can potentially sensitize these cells to chemotherapy drugs and radiation.

The unique mechanisms of DNA repair pathways in breast cancer stem cells are unknown. We proposed to use breast cancer stem cell-based model and assay systems to identify targets in the DNA repair pathways that can be used to sensitize breast cancer stem cells to chemotherapy and radiotherapy. By using the human RNA interference (RNAi) approach, we identified several targets in the DNA repair pathways promoting the repair activities in breast cancer stem cells. These pathways include: already recognized DNA repair pathways (e.g. PARP1), chromatin remodeling (e.g. HDAC1,2), and “stemness” factors (e.g., Notch4). In additional work, we examined multiple clinical trial stage HDAC inhibitors to sensitize breast cancer stem cells to chemo-drugs and radiation. We also found that the "combined treatment" using HDAC inhibitors and newly identified "targets" can achieve synergistic effects to sensitize breast cancer stem cells to radiation and chemo-drugs.

Targeting breast cancer stem cells may provide a way to prevent recurrence and have a huge impact on breast cancer treatment. Our research thus has a great potential leading to new therapeutic interventions for the effective treatment of breast cancer.