Abstract 3484: Distinct cancer cell with stem cell like properties contribute to doxorubicin and paclitaxel resistance

Abstract

Abstract Resistance to therapy and disease relapse is major concerns in the field of breast cancer management. Accumulating evidence suggests the existence of breast cancer stem cells and it has been proposed that their induction after chemotherapy could be contributing to therapy resistance and relapse. Our preliminary data demonstrate that expression of CXCL1 and CXCL8 (CXCR1/2 ligands) increases after chemotherapy. We also observed that expression of RANKL (ligand of RANK) goes up in a dose dependent manner in both Cl66 and 4T1 cells after treatment with paclitaxel and doxorubicin. Recently, the involvement of RANK/RANKL signaling in mammary tumorigenesis by maintaining the stem cell pool has been elucidated. Given that RANK-RANKL signaling and CXCR1/2 signaling share the common mediator, NFkB, our working hypothesis is that chemotherapy-induced expression of CXCR1/2 ligands and the RANK/RANKL signaling axis plays an important role in selecting a subset of mammary tumor cells with stem cell-like characteristics. We selected Cl66, mammary tumor cells against doxorubicin and paclitaxel. We observed that cells selected against these drugs express higher levels of CXCR1/2 ligands at both the mRNA and protein level. Moreover, 4T1 (6-thioguanine resistant cells) and Cl66 Dox 500 (cells resistant to doxorubicin) express RANK whereas Cl66-parent and Cl66 Pac 400 (cells resistant to paclitaxel) do not. This suggests that doxorubicin specifically selects RANK expressing cancer cells and 4T1 inherently express this receptor. Cl66 resistant cells injected in BALB/c mice grew slower than parent cells. Furthermore, the extent of neovascularization in doxorubicin resistant Cl66 tumors was significantly higher as compared to parent Cl66 tumors and paclitaxel resistant Cl66 tumors. As a result of their slow growth and difference in neovascularization, we analyzed the expression of stem cell markers in these cells. We observed that both Cl66-parent and paclitaxel resistant cells express ALDH1, but the expression was higher in paclitaxel resistant cells. Moreover, resistant cells showed enhanced expression of the mesenchymal marker, vimentin in comparison to parent cells. Overall, our results suggest that use of a particular chemotherapeutic agent may influence the selection of different sub-type of cancer cells with stem cell-like properties. This data also proposes the importance of a chemotherapy-induced cytokine-chemokine axis in maintaining the cancer stem cell pool. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3484. doi:1538-7445.AM2012-3484