雌激素受体阴性[ER(-)]乳腺癌是最具侵袭性的乳腺癌(BC)类型，具有较高的转移率和复发率。近年来，利用表观遗传活性植物化学物质通过饮食预防乳腺癌因其可行性、有效性和易于实施而受到越来越多的关注。在这方面，组合植物化学干预通过同时针对多种致瘤途径来实现更有效的 BC 抑制。因此，我们重点研究富含萝卜硫素 (SFN) 的西兰花芽 (BSp) 和富含醉茄素 A (WA) 的 Ashwagandha (Ash) 组合对雌激素受体阴性 [ER(-)] 乳腺乳腺癌预防的作用使用转基因小鼠进行癌症治疗。我们的结果表明，与对照治疗相比，BSp  Ash 组合治疗显着降低了肿瘤发生率和肿瘤生长 (~ 75%)，并延迟 (~ 21%) 肿瘤潜伏期，并且与对照治疗相比，BSp  Ash 组合治疗在抑制 BC 方面具有统计学上更有效的效果。单一 BSP 或 Ash 干预。在分子水平上，BSp 和 Ash 组合上调肿瘤抑制因子（p53、p57）以及凋亡相关蛋白（BAX、PUMA）和 BAX:BCL-2 比率。此外，我们的结果表明，由于组合治疗，乳腺肿瘤组织中表观遗传机制 HDAC1 和 DNMT3A 的表达下降。有趣的是，我们报道了 BSp 和 Ash 之间的多种协同相互作用，由于 BSp 和 Ash 的组合治疗，这些相互作用影响了肿瘤表型和分子表达。我们的 RNA-seq 分析结果还表明，由于 BSp 和 Ash 联合给药，与多种细胞信号通路、转录因子活性和表观遗传调控相关的基因在转录组范围内发生了表达重组。此外，我们发现联合治疗导致肠道微生物组成发生变化。总体而言，BSp 和 Ash 的组合补充可以通过增强肿瘤抑制、细胞凋亡诱导和基因表达的转录组范围内的重组来预防 ER(-) BC，这可能会影响多种细胞信号通路、表观遗传调控和重塑肠道微生物群。© 2024。 ）。

Estrogen receptor-negative [ER(-)] mammary cancer is the most aggressive type of breast cancer (BC) with higher rate of metastasis and recurrence. In recent years, dietary prevention of BC with epigenetically active phytochemicals has received increased attention due to its feasibility, effectiveness, and ease of implementation. In this regard, combinatorial phytochemical intervention enables more efficacious BC inhibition by simultaneously targeting multiple tumorigenic pathways. We, therefore, focused on investigation of the effect of sulforaphane (SFN)-rich broccoli sprouts (BSp) and withaferin A (WA)-rich Ashwagandha (Ash) combination on BC prevention in estrogen receptor-negative [ER(-)] mammary cancer using transgenic mice. Our results indicated that combinatorial BSp + Ash treatment significantly reduced tumor incidence and tumor growth (~ 75%) as well as delayed (~ 21%) tumor latency when compared to the control treatment and combinatorial BSp + Ash treatment was statistically more effective in suppressing BC compared to single BSp or Ash intervention. At the molecular level, the BSp and Ash combination upregulated tumor suppressors (p53, p57) along with apoptosis associated proteins (BAX, PUMA) and BAX:BCL-2 ratio. Furthermore, our result indicated an expressional decline of epigenetic machinery HDAC1 and DNMT3A in mammary tumor tissue because of combinatorial treatment. Interestingly, we have reported multiple synergistic interactions between BSp and Ash that have impacted both tumor phenotype and molecular expression due to combinatorial BSp and Ash treatment. Our RNA-seq analysis results also demonstrated a transcriptome-wide expressional reshuffling of genes associated with multiple cell-signaling pathways, transcription factor activity and epigenetic regulations due to combined BSp and Ash administration. In addition, we discovered an alteration of gut microbial composition change because of combinatorial treatment. Overall, combinatorial BSp and Ash supplementation can prevent ER(-) BC through enhanced tumor suppression, apoptosis induction and transcriptome-wide reshuffling of gene expression possibly influencing multiple cell signaling pathways, epigenetic regulation and reshaping gut microbiota.© 2024. The Author(s).