Abstract 5363: New targeted therapy on SOCS1-related immune-response in triple-negative breast cancer
Authors: Imoto Shigeru , Chiba Tomohiro , Seki Hirohito , Ishizaka Yoshiharu , Tsuchiya Ai , Kitaoka Tomoko 
Published: March 2024

Background: Triple-negative breast cancer (TNBC) is heterogenous, which includes basal-like, immunomodulatory, mesenchymal, mesenchymal stem cell and luminal androgen receptor subtypes. In addition to chemotherapy, PARP inhibitors and immune checkpoint inhibitors are effective for TNBC with BRCA-mutated and PD-L1-positive cases. However, overall survival of TNBC remains unfavorable. To explore new targeted therapy in TNBC, we reported previously that SOCS1 (suppressor of cytokine signaling 1), IL-13 and several genes were predicted as interactive targets of miRNA in TNBC from the microarray expression analysis (Agilent Technologies, Inc.) of small RNA extracted from 11 breast cancer specimens (AACR2020, #1709). Thus, we investigated SOCS1-related immune-response under co-culture of TNBC and monocyte cell lines with or without paclitaxel exposure.

Materials and Methods: MDA-MB-231, MDA-MB-468, RAW264.7 cell lines were used with co-culture system (Falcon® Cell Culture Inserts, Corning, NY, USA). SOCS1-expression vector and siSOCS1 were transfected into TNBC cell lines with polyethylenimine (PEI Max; Polysciences, Inc., Warrington, PA). RAW264.7 was activated with lipopolysaccaride (5ug/ml) and IFNγ (10ng/ml) for 2 days before co-culture. Relative cell viability of TNBC cell lines with vehicle control (DMSO) or paclitaxel exposure was measured with WST-8 (Cell Counting Kit-8; Dojindo, Japan) using TC20 Automated cell counter (Bio-Rad Laboratories, Inc., Japan) after 2 days’ co-culture of TNBC and RAW264.7 cells under several conditions of SOCS1 overexpression and/or RAW264.7 activation.

Results: First, paclitaxel inhibited cell growth of MDA-MB-231 and MDA-MB-468 in a dose-dependent manner (at 1nM~100nM). Second, at paclitaxel exposure of 10 nM and 50 nM, relative cell viability of MDA-MB-468 decreased with co-culture of activated RAW264.7. The tendency was enhanced with SOCS1 overexpression in breast cancer cell lines. Similar results were observed in MDA-MB-231 cells.

Discussions: SOCS1 is well known as a negative regulator of JAK-STAT pathway. SOCS1 is also related to suppression of T cell activation and modulation of M1 macrophage. At AACR2020, we reported that SOCS1 gene amplification in cancer tissues after neoadjuvant chemotherapy was relatively lower in 6 cases with pathologically partial or complete response than in 11 cases with no pathological response. In vitro, paclitaxel-toxicity in TNBC cells was augmented by activated monocyte (M1 macrophage) and more sensitized with SOCS1 overexpression in TNBC cells. These results suggest that proinflammatory cytokines from M1 macrophage influence cell viability of TNBC.

Conclusion: SOCS1 is a promising molecular target to modulate immune-response in TNBC.

Citation Format: Shigeru Imoto, Tomohiro Chiba, Hirohito Seki, Yoshiharu Ishizaka, Ai Tsuchiya, Tomoko Kitaoka. New targeted therapy on SOCS1-related immune-response in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5363.