Girithar Hemaasri-Neya, Krishnamurthy Shivani, Carroll Luke, Guller Anna, Bilgin Ayse A, Gluch Laurence, Guillemin Gilles J, Ahn Seong Beom, Heng Benjamin
Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
Australian Proteome Analysis Facility, Faculty of Science and Engineering, Macquarie University, Sydney, NSW, Australia.
Br J Cancer. 2024 Dec;131(12):1881-1892. doi: 10.1038/s41416-024-02889-z. Epub 2024 Nov 18.
Metastasis remains the major cause of death in breast cancer (BrCa) and lacks specific treatment strategies. The kynurenine pathway (KP) has been suggested as a key mechanism facilitating progression of BrCa. While KP activity has been explored in primary BrCa, its role in metastasis remains unclear. To better understand this, we examined changes in the KP of BrCa with no metastasis compared to BCa that produced local or distant metastases. Given that the cancer cell secretome plays a role in metastasis, we also investigated the relationship between changes in KP activity and serum proteins of patients with local or distant metastases.
To investigate changes in the KP in BrCa, with and without metastasis, we quantified KP metabolites in blood sera collected from patients with stage 1 BrCa (n = 34), BrCa with local metastases (n = 46), BrCa with distant metastases (n = 20) and healthy controls (n = 39). The serum protein profile of the BrCa patients with local or distant metastasis was determined before correlation analyses were carried out to examine the relationship between changes in the KP and cancer serum proteins using SPSS.
We found that the KP was elevated in BrCa patients with local and distant metastasis compared to healthy controls and stage 1 BrCa patients. The activity of kynurenine monooxygenase (KMO) and kynureninase (KYNU) A was positively associated with disease stage and was higher compared to healthy controls. Proteome analysis in patients with local or distant metastasis revealed the dysregulation of 14 proteins, 9 of which were up-regulated and 5 down-regulated at the distant metastasis stage. Importantly, three of these proteins have not been previously linked to BrCa metastasis. In the correlation studies between the KP profile, cancer serum proteins and metastasis status, KYNU A had the greatest number of significant associations with cancer serum protein, followed by KMO.
Our findings reveal that the KP was regulated differently at various stages of BrCa and was more dysregulated in patients with local or distant metastasis. These KP activity changes showed a significant association with cancer serum proteins in BrCa patients with local or distant metastasis, highlighting the potential role of KP in BrCa metastasis.
转移仍然是乳腺癌（BrCa）死亡的主要原因，且缺乏特异性治疗策略。犬尿氨酸途径（KP）被认为是促进BrCa进展的关键机制。虽然已在原发性BrCa中探索了KP活性，但其在转移中的作用仍不清楚。为了更好地理解这一点，我们比较了无转移的BrCa与发生局部或远处转移的BrCa中KP的变化。鉴于癌细胞分泌组在转移中起作用，我们还研究了局部或远处转移患者的KP活性变化与血清蛋白之间的关系。
为了研究有转移和无转移的BrCa中KP的变化，我们对从I期BrCa患者（n = 34）、有局部转移的BrCa患者（n = 46）、有远处转移的BrCa患者（n = 20）和健康对照者（n = 39）采集的血清中的KP代谢物进行了定量。在进行相关性分析以检查KP变化与癌症血清蛋白之间的关系之前，先确定了有局部或远处转移的BrCa患者的血清蛋白谱，分析使用SPSS软件进行。
我们发现，与健康对照者和I期BrCa患者相比，有局部和远处转移的BrCa患者的KP升高。犬尿氨酸单加氧酶（KMO）和犬尿氨酸酶（KYNU）A的活性与疾病分期呈正相关，且高于健康对照者。对有局部或远处转移患者的蛋白质组分析显示14种蛋白质失调，其中9种在远处转移阶段上调，5种下调。重要的是，这些蛋白质中有三种以前未与BrCa转移相关联。在KP谱、癌症血清蛋白和转移状态的相关性研究中，KYNU A与癌症血清蛋白的显著关联数量最多，其次是KMO。
我们的研究结果表明，BrCa的各个阶段对KP的调节不同，在有局部或远处转移的患者中失调更明显。这些KP活性变化与有局部或远处转移的BrCa患者的癌症血清蛋白显著相关，突出了KP在BrCa转移中的潜在作用。
