G protein-coupled KISS1 receptor is overexpressed in triple negative breast cancer and promotes drug resistance

Abstract

Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor α, progesterone receptor and human epidermal growth factor receptor 2 (HER2). TNBC patients lack targeted therapies, as they fail to respond to endocrine and anti-HER2 therapy. Prognosis for this aggressive cancer subtype is poor and survival is limited due to the development of resistance to available chemotherapies and resultant metastases. The mechanisms regulating tumor resistance are poorly understood. Here we demonstrate that the G protein-coupled kisspeptin receptor (KISS1R) promotes drug resistance in TNBC cells. KISS1R binds kisspeptins, peptide products of the KISS1 gene and in numerous cancers, this signaling pathway plays anti-metastatic roles. However, in TNBC, KISS1R promotes tumor invasion. We show that KISS1 and KISS1R mRNA and KISS1R protein are upregulated in TNBC tumors, compared to normal breast tissue. KISS1R signaling promotes drug resistance by increasing the expression of efflux drug transporter, breast cancer resistance protein (BCRP) and by inducing the activity and transcription of the receptor tyrosine kinase, AXL. BCRP and AXL transcripts are elevated in TNBC tumors, compared to normal breast, and TNBC tumors expressing KISS1R also express AXL and BCRP. Thus, KISS1R represents a potentially novel therapeutic target to restore drug sensitivity in TNBC patients.

KISS1/KISS1R and Breast Cancer: Metastasis Promoter

“…19,63 In support of this, KISS1/KISS1R mRNA and protein levels were found to be upregulated in primary tumor biopsies compared with healthy breast tissue and KISS1 and KISS1R protein was found to be immunolocalized in invasive ductal carcinoma in TNBC tumors. 65 Taken together, the presence of ERα in breast epithelia appears to critically regulate the expression of KISS1/KISS1R.…”

“…Metastatic breast cancer cells such as TNBC cells, MDA-MB-231, and Hs578T exhibit high expression of KISS1 and KISS1R in contrast to weakly invasive, ERα-positive breast cancer cells (T47D, MCF7) or nonmalignant breast MCF10A cells. 65 Depletion of KISS1R in TNBC cells using RNA interference reduced the expression of mesenchymal markers and stress-fiber formation and impaired invadopodia formation concurrent with their ability to migrate or invade. 72 Normal cells, in contrast to transformed cells, depend on cell to ECM contact to be able to grow and divide.…”

“…Using several TNBC cell lines (MDA-MB-231, Hs578t, SCP2, and SUM159) and ERα-negative cells (MCF10A, SKBR3), 19,65,72,[75][76][77] KISS1R signaling has been shown to promote cell migration and invasion, vital processes for metastasis. These have been observed in response to stimulating cells with KP-10.…”

“…Using a gain-of-function model, the overexpression of human KISS1R in ERα-negative cells, normal MCF10A cells, and SKBR3 breast cancer cells (which have low levels of endogenous KISS1R) also induced cell migration and invasion. 19,65 Furthermore, KISS1R overexpression in SKBR3 cells triggered tumor cells extravasation using the chick chorioallantoic membrane assay. KP-10 treatment of cells further increased the number of tumor cells that extravasated into the stroma, whereas a KISS1R antagonist (P-234) blocked the KP-10-mediated effect.…”

“…90,91 KISS1R signaling has been shown to induce chemoresistance in TNBC cells and multiple ERα-negative breast cancer cells by two mechanisms. 65 First, KISS1R modulates the expression of the ATP-binding cassette drug efflux transporter, breast cancer resistance protein (BCRP), a major multidrug-resistant transporter in TNBC. 92,93 Second, KP-10 treatment of cells activates the tyrosine kinase, AXL, 65 a binding partner of EGFR that is highly expressed in TNBC.…”