Abstract 1930: Low surface Gal3 expression in breast cancer stem cells is associated with chemoresistance, tumorigenesis, and decreased overall patient survival

Abstract

Abstract The development of therapeutic approaches that target specific breast cancer subtypes has improved overall survival, but some patients nevertheless become resistant to treatment and develop metastatic disease. Recent insights suggest multiple hallmarks of cancer - especially drug-resistance, unlimited self-renewal, as well as invasion and metastasis - that can be attributed to a small subpopulation frequently designated as cancer stem cells (CSC). CSCs are rare, self-renewing cells that initiate and maintain tumor growth. Galectin-3 (Gal3), a multifunctional oncogenic beta-galactoside binding lectin, was implicated in the metastatic cascade by aiding the homing of breast cancer circulating tumor cells to the metastatic niche. In addition, it was proposed that Gal3 protects breast cancer cells from mitochondria-dependent apoptosis induced by chemotherapeutic agents while concurrently promoting sensitivity to cell death ligands. Recently, we have found that in a subset of metastatic breast cancer cells (GI-LM2), cell-surface Gal3 is highly expressed compared to its non-metastatic counterpart (GI-101). Breast CSCs have been characterized by CD24-/CD44+/EpCAM+ surface marker expression in flowcytometry analysis. These subpopulations of GI-LM2 exhibit an enhanced self-renewal capability in sphere-formation assays (SFA) when compared to a similar subpopulation of GI-101. Surprisingly, depletion of Gal3 from this subset of GI-LM2 resulted in epithelial-mesenchymal-transition (EMT) - a mechanism linked to cancer stemness - as evidenced by Immunoblot and -fluorescence, resistance to the adjuvant FAC regimen (5-Fluorouracil, Doxorubicin, Cyclophosphamide), and markedly increased tumorigenicity in in vivo limited dilution assays. These findings are in keeping with results obtained from a stage 2 and 3a cohort of breast cancer patients (n=87) with axillary lymph node metastases. Gal3 expression in tissue microarrays from these patients was found to be significantly associated with the absence of lymphovascular invasion (p=0.015) as well as increased locoregional-free, disease-specific and overall survival (p=0.054, p=0.18, and p=0.019, respectively). Taken together, we present evidence in vitro, in vivo, and in clinico that lack of surface Gal3 in a subset of breast CSCs is associated with chemoresistance. This contrasts with earlier reports that Gal3 renders cancer cells chemoresistant, enhances tumorigenesis, and is associated with poor overall survival. Further studies will determine whether these finding can be applied to therapeutic stratification of breast cancer patients, or as a diagnostic tool for detection of circulating tumor cells which are frequently described as early indicators of dormant metastatic breast cancer. Citation Format: Matthias Illmer, Nachman Mazurek, James Byrd, Jody Vykoukal, Robert Scott Bresalier. Low surface Gal3 expression in breast cancer stem cells is associated with chemoresistance, tumorigenesis, and decreased overall patient survival. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1930. doi:10.1158/1538-7445.AM2014-1930