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Updated: Sep 13, 2025
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Targeting Triple-Negative Breast Cancer with Momordicine-I for Therapeutic Gain in Preclinical Models
Kousik Kesh1, Ellen T Tran1, Ruchi A Patel1
1Department of Pathology, Saint Louis University, St. Louis, MO 63104, USA.
Abstract:
Background: TNBC patients respond poorly to chemotherapy, leading to high mortality rates and a worsening prognosis. Here, we investigated the effect of M-I on TNBC tumor growth suppression and its potential mechanisms. Methods: Signaling pathways were analyzed to study the effect of M-I on TNBC cells (human MDA-MB-231 and mouse 4T1). We used orthotopic mouse models to examine the anti-tumor efficacy of M-I. Tumor volume and the status of tumor-associated macrophages (TAMs) were assessed by qRT-PCR or FACS analysis. Results: We found a significant dose- and time-dependent inhibition of TNBC cell proliferation following treatment with M-I. Cell cycle analysis revealed a shortened S phase in M-I-treated cells and downregulation of AURKA, PLK1, CDC25c, CDK1, and cyclinB1. Furthermore, M-I treatment reduced the expression of pSTAT3, cyclinD1, and c-Myc in TNBC cells. To evaluate the anti-tumor efficacy of M-I, we employed orthotopic TNBC mouse models and observed a significant reduction in tumor growth without measurable toxicity. Next, we analyzed RNA from control and M-I-treated tumors to further assess the status of TAMs and observed a significant decrease in M2-like macrophages in the M-I-treated group. Immortalized bone marrow-derived mouse macrophages (iMacs) exposed to conditioned media (CM) of TNBC cells with or without M-I treatment indicated that the M-I treated CM of TNBC cells significantly reduce the M2phenotype in iMacs. Mechanistically, we found that M-I specifically targets the IL-4/MAPK signaling axis to reduce immunosuppressive M2 macrophage polarization. Conclusions: Our study reveals a novel mechanism by which M-I inhibits TNBC cell proliferation by regulating intracellular signaling and altering TAMs in the tumor microenvironment and highlights its potential as a promising candidate for TNBC therapy.
Insights
M-I effectively suppresses triple-negative breast cancer (TNBC) cell growth by inhibiting key cell cycle proteins and reprogramming tumor-associated macrophages (TAMs). This study highlights M-I
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) exhibits poor response to chemotherapy, necessitating novel therapeutic strategies.
- Understanding the mechanisms underlying TNBC progression and immune evasion is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the anti-tumor effects of M-I on TNBC.
- To elucidate the molecular mechanisms by which M-I inhibits TNBC growth and modulates the tumor microenvironment.
Main Methods:
- In vitro analysis of TNBC cell lines (MDA-MB-231, 4T1) treated with M-I.
- Orthotopic mouse models of TNBC to assess in vivo anti-tumor efficacy.
- Flow cytometry and qRT-PCR to analyze tumor-associated macrophages (TAMs) and signaling pathways (e.g., pSTAT3, IL-4/MAPK).
Main Results:
- M-I demonstrated dose- and time-dependent inhibition of TNBC cell proliferation.
- M-I treatment led to cell cycle arrest, downregulation of key proliferation markers (AURKA, PLK1, CDK1, cyclin B1), and reduced pSTAT3, cyclin D1, and c-Myc expression.
- In vivo studies showed significant tumor growth reduction with M-I treatment, without observable toxicity, and a decrease in immunosuppressive M2-like TAMs.
Conclusions:
- M-I inhibits TNBC cell proliferation by targeting intracellular signaling pathways.
- M-I modulates TAMs, specifically reducing M2 polarization via the IL-4/MAPK axis, thereby overcoming tumor-induced immunosuppression.
- M-I represents a promising therapeutic candidate for TNBC, offering a novel approach by targeting both cancer cells and the tumor microenvironment.
