Abstract 5437: miR-302b as adjuvant therapeutic tool to improve chemotherapy efficacy in human triple-negative breast cancer

Abstract

Abstract Introduction: Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancer cases, with the worst outcome of all subtypes. For TNBC, still lacking targeted therapies, the only therapeutic option is currently chemotherapy, and despite a good initial response, patients often develop drug resistance. MiRNAs can modulate chemoresistance by affecting DNA repair, cell cycle progression, apoptosis and also tumor microenvironment. Macrophages constitute a major component of the immune microenvironment of cancer and pro-tumor M2 macrophages have been associated with resistance to chemotherapeutic treatments. Our previous data showed that miR-302b over-expression enhances sensitivity to cisplatin in breast cancer cell lines by targeting directly E2F1 and indirectly ATM. Here, we investigated the potential of miR-302b as a therapeutic tool to enhance cisplatin response in a TNBC mouse model and which pathways are involved in this mechanism both in tumor cells and microenvironment. Moreover, miR-302b prognostic value was assessed in a cohort of TNBC patients with available clinical outcome . Finally, we evaluated if miR-302b enhances the sensitivity to doxorubicin, another chemotherapeutic agent used as first-line therapy in TNBC patients. Material and method: MDA-MB-231 TNBC cells were injected into the mammary fat pad of female SCID mice and then treated with lipid nanoparticles containing miR-302b or cel-miR-67 control, alone or in combination with cisplatin. Gene expression profile on collected tumors was performed by microarray and tumor sections were stained with anti-arginase 1 (M2 marker) to evaluate the number of M2 macrophages. MiR-302b expression was assessed in 39 TNBC treated with chemotherapy in adjuvant setting, and associated with prognosis. Finally, MDA-MB-231 cells were transfected with miR-302b precursor or control treated with doxorubicin for 24h and then assessed for cell viability. Results: Our results show that miR-302b combination with cisplatin significantly impaired tumor growth in comparison with cel-67 control and cisplatin (p= 0.03), and reduced the number of M2 macrophages in the tumor microenvironment (p=0.005). Moreover, gene expression profile of collected tumors confirm immune system modulation. Notably, miR-302b expression was associated with disease-free survival and overall survival in TNBC patients treated with adjuvant chemotherapy. Furthermore, we found that miR-302b also enhances sensitivity to doxorubicin in vitro, affecting cell viability and cell cycle transition through E2F1 regulation. Conclusion: Our data demonstrate that miR-302b can be exploited as a new therapeutic tool to improve the response to chemotherapy, modulating tumor microenvironment. Moreover, this miRNA has prognostic significance in TNBC patients, and might also represent an useful predictive biomarker for response to chemotherapy. Citation Format: Alessandra Cataldo, Ilaria Plantamura, Elvira D'Ippolito, Sandra Romero-Cordoba, Sara Baroni, Valeria Cancilia, Claudio Tripodo, Dario Palmieri, Marilena V. Iorio. miR-302b as adjuvant therapeutic tool to improve chemotherapy efficacy in human triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5437. doi:10.1158/1538-7445.AM2017-5437