Abstract
Breast cancer is a leading cause of cancer mortality. In particular, triple negative breast cancer (TNBC) comprise a heterogeneous group of basal-like tumors lacking estrogen receptor (ERα), progesterone receptor (PR) and HER2 (ErbB2). TNBC represents 15–20% of all breast cancers and occurs frequently in women under 50 years of age. Unfortunately, these patients lack targeted therapy, are typically high grade and metastatic at time of diagnosis. The mechanisms regulating metastasis remain poorly understood. We have previously shown that the kisspeptin receptor, KISS1R stimulates invasiveness of TNBC cells. In this report, we demonstrate that KISS1R signals via the secreted extracellular matrix protein, fibulin-3, to regulate TNBC invasion. We found that the fibulin-3 gene is amplified in TNBC primary tumors and that plasma fibulin-3 levels are elevated in TNBC patients compared to healthy subjects. In this study, we show that KISS1R activation increases fibulin-3 expression and secretion. We show that fibulin-3 regulates TNBC metastasis in a mouse experimental metastasis xenograft model and signals downstream of KISS1R to stimulate TNBC invasion, by activating matrix metalloproteinase 9 (MMP-9) and the MAPK pathway. These results identify fibulin-3 as a new downstream mediator of KISS1R signaling and as a potential biomarker for TNBC progression and metastasis, thus revealing KISS1R and fibulin-3 as novel drug targets in TNBC.
Highlights
Breast cancer is the most common cancer in women, worldwide [1]
We demonstrate that the extracellular matrix (ECM) protein fibulin-3 regulates Triple negative breast cancer (TNBC) metastasis in mouse models and signals downstream of kisspeptin 1 receptor (KISS1R) to stimulate TNBC cell migration and invasion, shedding light on whether TNBC cells employ KISS1R signaling via fibulin-3 to attain metastatic potential
Fibulin-3 mRNA is overexpressed in effusions of human breast cancer patients [18], and fibulin-3 has been shown to promote breast tumor growth using animal models [17], whether plasma fibulin-3 levels differ in TNBC patients at different stage of disease is unknown
Summary
Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype, occurring often in women under 50 years of age or patients with BRCA1/ BRCA2 mutation [2]. TNBC patients have poor prognosis compared to other breast cancer subtypes. This can be attributed to the high incidence of disseminated tumor cells, leading to the onset of metastatic disease and associated morbidity [5,6,7]. To overcome this clinical problem, there is an urgent need to identify drug targets that are effective in treating metastatic TNBC
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