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Abstract：
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.
摘要：
雌激素受体阴性[ER（-）]乳腺癌是最具侵袭性的乳腺癌（BC）类型，具有较高的转移和复发率。近年来,饮食预防BC与表观遗传活性植物化学物质受到越来越多的关注，由于其可行性，有效性,和易于实施。在这方面,组合植物化学干预通过同时靶向多个致瘤途径来实现更有效的BC抑制。我们,因此,重点研究了富含萝卜硫素（SFN）的西兰花芽（BSp）和富含维生素A（WA）的Ashwagandha（Ash）组合对雌激素受体阴性[ER（-）]乳腺癌的BC预防的影响使用转基因小鼠。我们的结果表明，与对照治疗相比，组合BSp+Ash治疗显着降低了肿瘤发生率和肿瘤生长（〜75％）以及延迟（〜21％）的肿瘤潜伏期，并且组合BSp+Ash治疗在统计学上更有效地抑制BC与单一BSp或Ash干预相比。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，由于联合治疗，表观遗传机制HDAC1和DNMT3A在乳腺肿瘤组织中的表达下降。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的联合治疗,这些相互作用影响了肿瘤表型和分子表达.我们的RNA-seq分析结果还证明了与多个细胞信号通路相关的基因的全转录组表达重组。由于BSp和Ash联合施用，转录因子活性和表观遗传调控。此外,我们发现，由于组合治疗，肠道微生物组成的改变。总的来说,联合补充BSp和Ash可以通过增强肿瘤抑制来预防ER（-）BC，凋亡诱导和基因表达的全转录组重组可能影响多个细胞信号通路，表观遗传调控与肠道微生物群重塑。
