Department of Physiology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Pretoria 0031, South Africa.
Centre for Neuroendocrinology, Department of Immunology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Pretoria 0031, South Africa.
Int J Mol Sci. 2022 Aug 6;23(15):8744. doi: 10.3390/ijms23158744.
Kisspeptin is an anti-metastatic mediator in many cancer types, acting through its receptor, KISS1R. However, controversy remains regarding its role in breast cancer since both pro- and anti-metastatic roles have been ascribed to it. In KISS1R overexpressing triple-negative breast cancer (TNBC) cells, stimulation has been associated with increased invasion and MMP-9 expression, leading to the suggestion that hormone receptor status determines the metastatic effects of kisspeptin. To assess the veracity of this claim, we compared endogenous KISS1R signalling and physiological output in the hormone receptor-negative MDA-MB-231 and BT-20 cell lines after KP-10 (shortest active kisspeptin peptide) stimulation. MDA-MB-231 cells are metastatic when implanted in mice while BT-20 are not and remain epithelial-like. We show that both cell lines express mRNA and respond to KP-10 by elevating calcium mobilisation. However, KP-10 stimulation induced migration of MDA-MB-231, but not BT-20 cells, in a calcium-dependent manner. Moreover, only BT-20 cells responded to KP-10 by increasing ERK phosphorylation in a β-arrestin-dependent manner. Interestingly, both cell lines displayed different complements of β-arrestin 1 and 2 expression. Overall, our data shows that, in TNBC, it is not universally true that kisspeptin/KISS1R stimulate migration or pro-metastatic behaviour, as divergent responses were observed in the two TNBC lines tested. Whether this divergence is related to the observed differences in β-arrestin complements warrants further investigation and may enable further stratification of the ability of kisspeptin to influence breast tumour behaviour.
kisspeptin 是许多癌症类型中的一种抗转移介质，通过其受体 KISS1R 发挥作用。然而，由于 kisspeptin 被赋予了促转移和抗转移作用，因此其在乳腺癌中的作用仍存在争议。在 KISS1R 过表达的三阴性乳腺癌（TNBC）细胞中，刺激与侵袭增加和 MMP-9 表达增加有关，这导致人们认为激素受体状态决定了 kisspeptin 的转移作用。为了评估这一说法的真实性，我们比较了激素受体阴性 MDA-MB-231 和 BT-20 细胞系中内源性 KISS1R 信号和生理输出在 KP-10（最短活性 kisspeptin 肽）刺激后的情况。当 MDA-MB-231 细胞被植入小鼠中时，它们具有转移性，而 BT-20 细胞则没有，并且保持上皮样。我们表明，两种细胞系都表达 mRNA，并通过升高钙动员对 KP-10 作出反应。然而，只有 MDA-MB-231 细胞在钙依赖性方式下对 KP-10 刺激产生迁移，而 BT-20 细胞则不会。此外，只有 BT-20 细胞通过 β-arrestin 依赖性方式对 KP-10 作出反应，增加 ERK 磷酸化。有趣的是，两种细胞系都显示出不同的 β-arrestin 1 和 2 表达。总的来说，我们的数据表明，在 TNBC 中，普遍来说， kisspeptin/KISS1R 并不一定会刺激迁移或促转移行为，因为在两种测试的 TNBC 系中观察到了不同的反应。这种差异是否与观察到的β-arrestin 补充剂的差异有关，这值得进一步研究，并且可能进一步分层 kisspeptin 影响乳腺癌行为的能力。
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