Abstract:
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 antimetastatic 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 KISS1R 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.
