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<p>Breast cancer progression is driven by aberrant signaling pathways that include proliferation, apoptosis, and cytoskeletal remodeling. While tamoxifen remains central to breast cancer therapy, its clinical utility is restricted by developing resistance and toxicity, prompting the need for safer alternatives. To this end, glycyrrhizin, a triterpenoid saponin derived from <i>Glycyrrhiza glabra</i>, has shown activity against different cancers, yet its exact role in breast carcinogenesis remains elusive. In the present study, the effects of glycyrrhizin and tamoxifen were evaluated in a 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary carcinoma model. Both treatments significantly delayed tumor onset, reduced incidence, and decreased overall tumor burden. Histopathology revealed that DMBA exposure produced predominantly high-grade adenocarcinomas, whereas preventive glycyrrhizin and tamoxifen markedly reduced tumor grade to well-differentiated lesions. Curative protocols using glycyrrhizin and tamoxifen eliminated high-grade features. Gene expression studies indicated downregulation of oncogenic drivers (<i>c-Myc</i>,<i> stathmin</i>,<i> cyclin D1</i>,<i> RAN</i>,<i> α-tubulin</i>) and suppression of the anti-apoptotic protein <i>Bcl-2</i>. Both agents increased <i>p53</i> mRNA expression, modulated <i>interferon-γ</i> expression, and decreased <i>HSP84</i> expression. Importantly, glycyrrhizin uniquely enhanced <i>PTEN</i> mRNA expression versus tamoxifen, suggesting a potential influence on PI3K/AKT-related signaling. Protein expression analysis of cyclin D1 and α-tubulin demonstrated reduced levels, consistent with disrupted cell-cycle progression along with compromised cytoskeletal integrity. Collectively, these findings indicate that glycyrrhizin exerts anticancer activity associated with modulation of multiple cancer-related genes and histopathological regression, with a distinctive impact on <i>PTEN</i> mRNA expression and cytoskeletal regulators. These data support glycyrrhizin as a promising natural compound for breast cancer and warrant further protein-level mechanistic and translational evaluation.</p>

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Glycyrrhizin upregulates PTEN and suppresses oncogenic signaling in breast cancer

  • 期刊论文

  • 发表日期：

    2026年1月20日

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  • Moneeb Ashraf,
  • Usman Aftab,
  • Tasleem Akhtar,
  • Ali Rafi,
  • Shoaib Ashraf,
  • Safdar Hussain,
  • Muhammad Shahzad

摘要

Breast cancer progression is driven by aberrant signaling pathways that include proliferation, apoptosis, and cytoskeletal remodeling. While tamoxifen remains central to breast cancer therapy, its clinical utility is restricted by developing resistance and toxicity, prompting the need for safer alternatives. To this end, glycyrrhizin, a triterpenoid saponin derived from Glycyrrhiza glabra, has shown activity against different cancers, yet its exact role in breast carcinogenesis remains elusive. In the present study, the effects of glycyrrhizin and tamoxifen were evaluated in a 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary carcinoma model. Both treatments significantly delayed tumor onset, reduced incidence, and decreased overall tumor burden. Histopathology revealed that DMBA exposure produced predominantly high-grade adenocarcinomas, whereas preventive glycyrrhizin and tamoxifen markedly reduced tumor grade to well-differentiated lesions. Curative protocols using glycyrrhizin and tamoxifen eliminated high-grade features. Gene expression studies indicated downregulation of oncogenic drivers (c-Myc, stathmin, cyclin D1, RAN, α-tubulin) and suppression of the anti-apoptotic protein Bcl-2. Both agents increased p53 mRNA expression, modulated interferon-γ expression, and decreased HSP84 expression. Importantly, glycyrrhizin uniquely enhanced PTEN mRNA expression versus tamoxifen, suggesting a potential influence on PI3K/AKT-related signaling. Protein expression analysis of cyclin D1 and α-tubulin demonstrated reduced levels, consistent with disrupted cell-cycle progression along with compromised cytoskeletal integrity. Collectively, these findings indicate that glycyrrhizin exerts anticancer activity associated with modulation of multiple cancer-related genes and histopathological regression, with a distinctive impact on PTEN mRNA expression and cytoskeletal regulators. These data support glycyrrhizin as a promising natural compound for breast cancer and warrant further protein-level mechanistic and translational evaluation.