College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
College of Life Sciences, Northeast Agricultural University, No. 600 Changjiang Road, Harbin, 150030, PR China.
Breast Cancer Res. 2024 Oct 25;26(1):147. doi: 10.1186/s13058-024-01904-8.
Obesity is an important risk factor for breast cancer in women before and after menopause. Adipocytes, key mediators in the tumor microenvironment, play a pivotal role in the relationship between obesity with cancer. However, the potential of dietary components in modulating this relationship remains underexplored. Genistein, a soy-derived isoflavone, has shown promise in reducing breast cancer risk, attenuating obesity-associated inflammation, and improving insulin resistance. However, there are no reports examining whether genistein has the ability to reduce the effects of obesity on breast tumor development. In this study, we constructed a mammary tumor model in ovariectomized obese mice and examined the effects of genistein on body condition and tumor growth. Moreover, the effects of genistein on the tumor microenvironment were examined via experimental observation of peritumoral adipocytes and macrophages. In addition, we further investigated the effect of genistein on adipocyte and breast cancer cell crosstalk via coculture experiments. Our findings indicate that dietary genistein significantly alleviates obesity, systemic inflammation, and metabolic disorders induced by a high-fat diet in ovariectomized mice. Notably, it also inhibits tumor growth in vivo. The impact of genistein extends to the tumor microenvironment, where it reduces the production of cancer-associated adipocytes (CAAs) and the recruitment of M2d-subtype macrophages. In vitro, genistein mitigates the transition of adipocytes into CAAs and inhibits the expression of inflammatory factors by activating PPAR-γ pathway and degrading nuclear NF-κB. Furthermore, it impedes the acquisition of invasive properties and epithelial‒mesenchymal transition in breast cancer cells under CAA-induced inflammation, disrupting the Wnt3a/β-catenin pathway. Intriguingly, the PPAR-γ inhibitor T0070907 counteracted the effects of genistein in the coculture system, underscoring the specificity of its action. Our study revealed that genistein can mitigate the adverse effects of obesity on breast cancer by modulating the tumor microenvironment. These findings provide new insights into how genistein intake and a soy-based diet can reduce breast cancer risk.
肥胖是绝经前和绝经后女性乳腺癌的一个重要危险因素。脂肪细胞作为肿瘤微环境中的关键调节因子，在肥胖与癌症之间的关系中起着关键作用。然而，饮食成分在调节这种关系方面的潜力仍未得到充分探索。染料木黄酮是一种来源于大豆的异黄酮，已被证明具有降低乳腺癌风险、减轻肥胖相关炎症和改善胰岛素抵抗的作用。然而，目前尚无研究报告检查染料木黄酮是否有能力减轻肥胖对乳腺肿瘤发展的影响。在这项研究中，我们构建了去卵巢肥胖小鼠的乳腺肿瘤模型，并研究了染料木黄酮对机体状况和肿瘤生长的影响。此外，通过观察肿瘤周围脂肪细胞和巨噬细胞的实验，研究了染料木黄酮对肿瘤微环境的影响。此外，我们还通过共培养实验进一步研究了染料木黄酮对脂肪细胞和乳腺癌细胞相互作用的影响。我们的研究结果表明，饮食中添加染料木黄酮可显著减轻去卵巢肥胖小鼠高脂饮食引起的肥胖、全身炎症和代谢紊乱。值得注意的是，它还能抑制体内肿瘤的生长。染料木黄酮的影响还扩展到肿瘤微环境，在肿瘤微环境中，它减少了癌症相关脂肪细胞（CAAs）的产生和 M2d 亚型巨噬细胞的募集。在体外，染料木黄酮通过激活 PPAR-γ 通路和降解核 NF-κB，减轻脂肪细胞向 CAAs 的转化，并抑制炎症因子的表达。此外，它阻止了在 CAA 诱导的炎症下乳腺癌细胞获得侵袭性和上皮-间充质转化，破坏了 Wnt3a/β-catenin 通路。有趣的是，PPAR-γ 抑制剂 T0070907 拮抗了共培养系统中染料木黄酮的作用，突出了其作用的特异性。我们的研究表明，染料木黄酮可以通过调节肿瘤微环境来减轻肥胖对乳腺癌的不利影响。这些发现为染料木黄酮摄入和大豆饮食如何降低乳腺癌风险提供了新的见解。
