P3-17-02: Targeting the Autophagy Pathway for Drug Resistance of Breast Tumor-Initiating Cells.

Background: Our clinical data and experimental evidence reveal that the tumor-initiating cells (TICs) in the original tumor are intrinsically resistant to conventional chemotherapy and radiation therapy and greatly enriched in residual breast cancers after such treatments. We have published a gene expression signature of such breast TICs, and our pathway analysis on the gene signature suggests that the activation of autophagy pathway may be an intrinsic characteristic of the TICs. This motivates us to further investigate the role of the autophagy pathway in TICs self-maintenance and their resistance to hormonal and chemo therapies, as well as their response to TIC-targeted therapies. Methods: A collective 84 well-documented autophagy pathway genes were used to compare the activation of autophagy pathway in different microarray datasets, 1) flow-sorted CD44 + /CD24 −/low cancer cells vs. all other cells (representing 20 patients), and cancer-derived MSs vs. corresponding primary bulk tumors (representing 17 patients), 2) before vs. after letrozole and doxetaxel treatments (representing 30 patient pairs), 3) before vs. after letrozole treatment (representing 176 patient pairs), and 4) before vs. after lapatinib treatment (representing 115 patient pairs). We applied the Significance Analysis of Microarrays (SAM) algorithm to analyze the expression data of 211 normalized probes for the 84 genes. Low-density RTPCR array for the 84 genes was used to confirm the differential expressed genes on tumor tissues of 18 letrozol treated patient pairs. Two human-cancer-in-mouse triple-negative xenograft tumor lines were treated with Notch pathway inhibitor alone or in combining with docetaxel. The tumor growth, mammosphere formation efficiency, and the expression of autophagy marker proteins were evaluated. Results: Overall, the enrichment analysis of the 84-gene set in all the above microarray datasets showed that the autophagy genes are significantly enriched in the differential expressed genes. In particular, 28 out of the 84 autophagy genes are significantly up-regulated in the TICs populations while 5 other autophagy genes are down-regulated with the false discovery rate (FDR) less than 0.05. For the letrozole and doxetaxel treatment microarray analysis, 34 out of the 84 autophagy genes are significantly up-regulated in the after-treatment group (p Conclusion: Activation of the autophagy pathway in TICs is a promising target to combat the drug resistance of breast cancer to conventional systemic therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-17-02.