Abstract
Abstract Currently, the main option for systemic therapy of high-risk breast cancer is chemotherapy, with an overall poor efficacy and severe side effects. Chemotherapy-resistance and incomplete pathologic response associate with risk of metastasis and early relapse in breast cancer. In order to characterize treatment-resistant tumor cells, we performed a cell surface marker screen in 4 triple-negative breast cancer patient-derived xenograft (PDX) models that respond well to adriamycin/cyclophosphamide-based chemotherapy but fail to reach complete pathological response. We used multi-parameter flow cytometry to screen for the expression of a set of 45 cell surface markers during the course of chemotherapy. This set of markers represented both proteins involved in stem cell function and proteins known to be over-expressed in stem cells or cancer stem cell sub-populations. We identified the sialyl-glycolipid SSEA4 as a constant marker of chemotherapy-resistant cancer cells in all four models. In addition, SSEA4 expression was found higher in 3 out of 4 TNBC PDXs that are de novo resistant to neo-adjuvant chemotherapy compared to sensitive TNBC PDXs. Two cell populations with different percentage of SSEA4-positive (SSEA4+) cells and with different growth characteristics were identified in a PDX model. When treated with genotoxic compounds, the cell population with higher SSEA4+ expression showed increased resistance to chemotherapy, indicating this post-translational modification as potential marker of tumor resistance. Comparison of SSEA4+ and SSEA4-negative (SSEA4-) tumor cells from TNBC PDX models by global gene expression profiling showed overexpression of mesenchymal-associated genes in SSEA4+ tumor cells and a deregulation of drug resistance pathway-associated genes and miRNAs. In addition, high expression of ST3 beta-galactoside alpha-2,3-sialyltransferase 2 (ST3GAL2), the enzyme catalyzing the last step of SSEA4 synthesis, was found associated with poor outcome in breast and ovarian cancer patients treated with chemotherapy. Thus, we propose SSEA4 as a novel marker of epithelial-mesenchymal transition associated with chemoresistance, and ST3GAL2 expression as a predictive marker for tumor chemoresistance associated with poor outcome in breast and ovarian cancer patients. Both biomarkers and additionally identified regulatory miRNAs may be used to further understand chemoresistance and to develop alternative treatment regimens for breast and ovarian cancer patients. Citation Format: Andrea Aloia, Evgeniya Petrova, Stefan Tomiuk, Ute Bissels, Sophie Banis, Olivier Deas, Silvia Rüberg, Bernhard Gerstmayer, David Agorku, Jean-Gabriel Judde, Andreas Bosio, Stefano Cairo, Olaf T. Hardt. The sialyl-glycolipid SSEA4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4317. doi:10.1158/1538-7445.AM2015-4317
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