RARRES2’s impact on lipid metabolism in triple-negative breast cancer: a pathway to brain metastasis,Military Medical Research

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RARRES2’s impact on lipid metabolism in triple-negative breast cancer: a pathway to brain metastasis
Military Medical Research ( IF 21.1 ) Pub Date : 2023-09-12 , DOI: 10.1186/s40779-023-00480-w
Quazi T H Shubhra _{1,

2}

Affiliation

Breast cancer brain metastasis (BCBrM) is a crucial and hard area of research which guarantees an urgent need to understand the underlying molecular mechanisms. A recent study by Li et al. [1] published in Military Medical Research investigated the role of retinoic acid receptor responder 2 (RARRES2) in regulating lipid metabolism in BCBrM, highlighting the clinical relevance of alterations in lipid metabolites, such as phosphatidylcholine (PC) and triacylglycerols (TAGs), by RARRES2 through the modulation of phosphatase and tensin homologue (PTEN)-mammalian target of rapamycin (mTOR)-sterol regulatory element-binding protein 1 (SREBP1) signaling pathway. This commentary aims to elaborate on the key findings and their relevance to the field.

As the leading cause of death worldwide, cancer shows varied pathological progression and demands high treatment costs, posing a significant challenge to global health [2]. Breast cancer (BC), which accounted for the highest number of new diagnoses in 2020 (2.26 million new cases), exemplifies the complexity of the fight again cancers. Among the subtypes of BC, triple-negative breast cancer (TNBC) is particularly aggressive, frequently metastasizing to the brain [3] and defying most existing treatment options. This makes the management of TNBC a formidable task, marked by its propensity for rapid metastasis and limited therapeutic avenues. In this landscape, the study by Li et al. [1] gains profound significance due to offering invaluable insights into the mechanisms that drive this cancer’s spread to the brain. The brain is unique because it’s made up of a lot of fats. The study dug deeper into how BC cells that spread to the brain adapt to this fatty environment. They found that a specific protein called RARRES2 helps these cancer cells fit into the brain by changing the way they handle fats. The research illuminates the potential role of RARRES2, not only as a predictive biomarker for metastasis but also as a key to unlocking novel therapeutic strategies for this relentless form of cancer.

In addition, Li et al. [1] investigated the significant role of RARRES2 in regulating lipid metabolism within MDA-MB-231 cells. This regulation appears to directly influence BCBrM. RARRES2 has been found to interfere with the biological processes of several key metabolites, particularly PC and TAGs. Interestingly, the knockdown of RARRES2 led to an increase in PC levels and a decrease in TAGs. This discovery is not merely of academic interest but reflects on the broader mechanisms underlying dysregulated brain’s lipid metabolism. The understanding of these mechanisms is essential to unraveling the complex interactions and dependencies that characterize BC progression. Previously it was known by scientists that RARRES2 influences obesity [4] and autoimmune diseases, but this study showed that it plays a part in BC spreading to the brain as well.

The study further illuminated the role of the PTEN-mTOR-SREBP1 signaling pathway, which emerged as an important player in the regulatory network of lipid metabolism. The significance of the phosphatidylinositol 3-kinase (PI3K)/mTOR axis and the downstream SREBP signaling were highlighted as key regulatory hubs in lipid metabolism. The relationship between RARRES2 and these signaling pathways was found to be inversely proportional. RARRES2 knockdown or RARRES2 overexpression varied the protein levels of p-Akt, mTOR, p-mTOR, and SREBP1/cleaved SREBP1, establishing RARRES2’s negative regulatory effect on the mTOR-SREBP1 pathway. This negative regulation plays a critical role in controlling the complex interplay of molecules within the cancerous cells of the MDA-MB-231 line.

Another layer of complexity in the study’s findings is the role of chemokine-like receptor-1 (CMKLR1), a primary receptor through which RARRES2 exerts its biological functions. CMKLR1 knockdown could alter PTEN expression and p-Akt levels, emphasizing its relevance in the RARRES2-mediated lipid metabolic reprogramming. This revelation further clarifies the multifaceted and intricate regulatory mechanisms at play within the BC cell’s lipid metabolism. Additionally, the established positive correlation between CMKLR1 and RARRES2 aligns with and builds upon previous work, thereby integrating this study seamlessly into the broader scientific discourse [5].

The therapeutic potential of these findings was demonstrated by using the drug rapamycin (an mTOR inhibitor). When RARRES2 knockdown cells were treated with rapamycin, the increased proliferation and invasion observed in these cells were significantly reversed. This result not only corroborates the pivotal role of RARRES2 in controlling the PTEN-mTOR-SREBP1 axis but also hints at the possibility of targeted interventions that could hinder BC growth and invasion.

BC remains a common malignancy, and its effective management is vital for the health and well-being of all communities, including military personnel. Understanding the role of RARRES2 and the associated signaling pathways could inform targeted treatment strategies. The study’s findings regarding the role of RARRES2 in regulating lipid metabolism in MDA-MB-231 cells, and its interaction with the PTEN-mTOR-SREBP1 signaling pathway, provide substantial insights into the underlying mechanisms of BC. These insights have potential therapeutic implications, opening doors for targeted treatments that may ultimately benefit global BC patients. By delving into the complexities of lipid metabolic reprogramming and the interactions between various signaling pathways, the research contributes valuable knowledge to the broader understanding of BC. These findings could lead to enhanced medical strategies, not only within oncology but also in the interdisciplinary collaboration between medical fields, with potential applications in military medicine.

Not applicable.

BC:: Breast cancer
BCBrM:: Breast cancer brain metastasis
CMKLR1:: Chemokine-like receptor-1
mTOR:: Mammalian target of rapamycin
PC:: Phosphatidylcholine
PTEN:: Phosphatase and tensin homologue
PI3K:: Phosphatidylinositol 3-kinase
RARRES2:: Retinoic acid receptor responder 2
SREBP:: Sterol regulatory element-binding protein
TAGs:: Triacylglycerols
TNBC:: Triple-negative breast cancer

Li YQ, Sun FZ, Li CX, Mo HN, Zhou YT, Lv D, et al. RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer. Mil Med Res. 2023;10(1):34.
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Authors and Affiliations

Institute of Chemistry, University of Silesia in Katowice, 41-500, Chorzów, Poland
Quazi T. H. Shubhra
Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
Quazi T. H. Shubhra

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Quazi T. H. ShubhraView author publications
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QTHS designed and wrote the manuscript. The author read and approved the final manuscript.

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Correspondence to Quazi T. H. Shubhra.

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The author declares that there is no competing interests.

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Shubhra, Q.T.H. RARRES2’s impact on lipid metabolism in triple-negative breast cancer: a pathway to brain metastasis. Military Med Res 10, 42 (2023). https://doi.org/10.1186/s40779-023-00480-w

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Received: 08 August 2023
Accepted: 06 September 2023
Published: 12 September 2023
DOI: https://doi.org/10.1186/s40779-023-00480-w

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Keywords

Retinoic acid receptor responder 2 (RARRES2)
Lipid metabolism
Cancer
PTEN-mTOR-SREBP1 signaling
Metabolic reprogramming
Brain metastasis

中文翻译：

RARRES2 对三阴性乳腺癌脂质代谢的影响：脑转移的途径

乳腺癌脑转移（BCBrM）是一个关键且困难的研究领域，迫切需要了解其潜在的分子机制。李等人最近的一项研究。[1] 发表在《军事医学研究》上，研究了视黄酸受体反应物 2 (RARRES2) 在调节 BCBrM 脂质代谢中的作用，强调了脂质代谢物（例如磷脂酰胆碱 (PC) 和三酰甘油 (TAG)）改变的临床相关性，通过RARRES2 通过调节磷酸酶和张力蛋白同源物 (PTEN)-哺乳动物雷帕霉素靶标 (mTOR)-甾醇调节元件结合蛋白 1 (SREBP1) 信号通路。本评论旨在详细阐述主要发现及其与该领域的相关性。

癌症作为全球主要死亡原因，其病理进展多样，治疗费用高昂，对全球健康构成重大挑战[2]。乳腺癌 (BC) 是 2020 年新诊断病例数最高的癌症（226 万新发病例），这体现了抗击癌症的复杂性。在 BC 的亚型中，三阴性乳腺癌 (TNBC) 的侵袭性特别强，经常转移至大脑 [3]，并且对大多数现有的治疗方案无效。这使得 TNBC 的管理成为一项艰巨的任务，其特点是具有快速转移的倾向和有限的治疗途径。在这种情况下，李等人的研究。[1] 由于对驱动这种癌症扩散到大脑的机制提供了宝贵的见解，因此具有深远的意义。大脑是独一无二的，因为它由大量脂肪组成。该研究更深入地研究了扩散到大脑的 BC 细胞如何适应这种脂肪环境。他们发现一种名为 RARRES2 的特定蛋白质通过改变癌细胞处理脂肪的方式来帮助这些癌细胞适应大脑。该研究阐明了 RARRES2 的潜在作用，它不仅作为转移的预测生物标志物，而且作为解锁这种无情癌症的新治疗策略的关键。

此外，李等人。[1] 研究了 RARRES2 在调节 MDA-MB-231 细胞内脂质代谢中的重要作用。该法规似乎直接影响 BCBrM。RARRES2 被发现会干扰几种关键代谢物的生物过程，特别是 PC 和 TAG。有趣的是，RARRES2 的敲除导致 PC 水平增加和 TAG 减少。这一发现不仅具有学术意义，而且反映了大脑脂质代谢失调的更广泛机制。了解这些机制对于阐明 BC 进展的复杂相互作用和依赖性至关重要。此前，科学家们已知 RARRES2 会影响肥胖 [4] 和自身免疫性疾病，但这项研究表明，它也在 BC 传播至大脑的过程中发挥着一定作用。

该研究进一步阐明了 PTEN-mTOR-SREBP1 信号通路的作用，该信号通路在脂质代谢调节网络中发挥着重要作用。磷脂酰肌醇 3 激酶 (PI3K)/mTOR 轴和下游 SREBP 信号传导作为脂质代谢的关键调节中心，具有重要意义。研究发现 RARRES2 与这些信号通路之间的关系呈反比关系。RARRES2 敲低或 RARRES2 过表达改变了 p-Akt、mTOR、p-mTOR 和 SREBP1/裂解的 SREBP1 的蛋白水平，确定了 RARRES2 对 mTOR-SREBP1 通路的负调节作用。这种负调控在控制 MDA-MB-231 系癌细胞内分子的复杂相互作用中发挥着关键作用。

该研究结果的另一层复杂性是趋化因子样受体-1 (CMKLR1) 的作用，它是 RARRES2 发挥其生物学功能的主要受体。CMKLR1 敲低可以改变 PTEN 表达和 p-Akt 水平，强调其与 RARRES2 介导的脂质代谢重编程的相关性。这一发现进一步阐明了 BC 细胞脂质代谢中多方面且复杂的调节机制。此外，CMKLR1 和 RARRES2 之间已建立的正相关性与之前的工作一致并建立在之前的工作基础上，从而将这项研究无缝地融入到更广泛的科学讨论中 [5]。

这些发现的治疗潜力通过药物雷帕霉素（一种 mTOR 抑制剂）得到了证明。当用雷帕霉素处理 RARRES2 敲低细胞时，在这些细胞中观察到的增殖和侵袭增加显着逆转。这一结果不仅证实了 RARRES2 在控制 PTEN-mTOR-SREBP1 轴中的关键作用，而且暗示了有针对性的干预措施可能阻碍 BC 的生长和侵袭。

BC 仍然是一种常见的恶性肿瘤，其有效管理对于包括军事人员在内的所有社区的健康和福祉至关重要。了解 RARRES2 的作用和相关信号通路可以为靶向治疗策略提供信息。该研究关于 RARRES2 在调节 MDA-MB-231 细胞脂质代谢中的作用及其与 PTEN-mTOR-SREBP1 信号通路的相互作用的发现，为 BC 的潜在机制提供了重要的见解。这些见解具有潜在的治疗意义，为靶向治疗打开了大门，最终可能使全球 BC 患者受益。通过深入研究脂质代谢重编程的复杂性以及各种信号通路之间的相互作用，该研究为更广泛地了解 BC 提供了宝贵的知识。这些发现可能会导致增强的医疗策略，不仅在肿瘤学领域，而且在医学领域之间的跨学科合作中，并在军事医学中具有潜在的应用。

不适用。

公元前：: 乳腺癌
BCBrM：: 乳腺癌脑转移
CMKLR1：: 趋化因子样受体1
米托：: 雷帕霉素的哺乳动物靶点
个人电脑：: 磷脂酰胆碱
PTEN：: 磷酸酶和张力蛋白同系物
PI3K：: 磷脂酰肌醇3-激酶
罕见2：: 视黄酸受体反应者2
SRBP：: 甾醇调节元件结合蛋白
标签：: 三酰甘油
三全国广播公司：: 三阴性乳腺癌

李YQ，孙福Z，李CX，莫HN，周YT，吕D，等。RARRES2 调节脂质代谢重编程以介导三阴性乳腺癌脑转移的发展。米尔医学研究中心。2023；10(1):34。
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文章 CAS 谷歌学术
Sirhan Z、Thyagarajan A、Sahu RP。基于图卡替尼的治疗方法对 HER2 阳性乳腺癌的疗效。米尔医学研究中心。2022；9(1):39。
CAS PubMed PubMed 中心 Google 学术搜索
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文章 CAS PubMed 谷歌学术
Rennier K、Shin WJ、Krug E、Virdi G、Pachynski RK。Chemerin 通过调节新型 CMKLR1 介导的信号级联反应重新激活 PTEN 并抑制肿瘤细胞中的 PD-L1。临床癌症研究中心。2020；26(18):5019–35。
文章 CAS PubMed 谷歌学术

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作者和单位

化学研究所，卡托维兹西里西亚大学，41-500，霍茹夫，波兰
夸齐·TH·舒布拉
武汉大学人民医院神经外科, 武汉, 430060
夸齐·TH·舒布拉

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