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KISS1 in metastatic cancer research and treatment: potential and paradoxes.

ABSTRACT: The significance of KISS1 goes beyond its original discovery as a metastasis suppressor. Its function as a neuropeptide involved in diverse physiologic processes is more well studied. Enthusiasm regarding KISS1 has cumulated in clinical trials in multiple fields related to reproduction and metabolism. But its cancer therapeutic space is unsettled. This review focuses on collating data from cancer and non-cancer fields in order to understand shared and disparate signaling that might inform clinical development in the cancer therapeutic and biomarker space. Research has focused on amino acid residues 68-121 (kisspeptin 54), binding to the KISS1 receptor and cellular responses. Evidence and counterevidence regarding this canonical pathway require closer look at the covariates so that the incredible potential of KISS1 can be realized.

SUBMITTER: Ly T

PROVIDER: S-EPMC7483209 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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KISS1 in metastatic cancer research and treatment: potential and paradoxes.

Ly Thuc T Harihar Sitaram S Welch Danny R DR

Cancer metastasis reviews 20200901 3

The significance of KISS1 goes beyond its original discovery as a metastasis suppressor. Its function as a neuropeptide involved in diverse physiologic processes is more well studied. Enthusiasm regarding KISS1 has cumulated in clinical trials in multiple fields related to reproduction and metabolism. But its cancer therapeutic space is unsettled. This review focuses on collating data from cancer and non-cancer fields in order to understand shared and disparate signaling that might inform clinic ...[more]

PMID: 32152912

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Project description:BackgroundEndocrine therapy remains the mainstay of treatment for estrogen receptor-positive (ER+) breast cancer. Constitutively active mutations in the ligand binding domain of ERα render tumors resistant to endocrine agents. Breast cancers with the two most common ERα mutations, Y537S and D538G, have low sensitivity to fulvestrant inhibition, a typical second-line endocrine therapy. Lasofoxifene is a selective estrogen receptor modulator with benefits on bone health and breast cancer prevention potential. This study investigated the anti-tumor activity of lasofoxifene in breast cancer xenografts expressing Y537S and D538G ERα mutants. The combination of lasofoxifene with palbociclib, a CDK4/6 inhibitor, was also evaluated.MethodsLuciferase-GFP tagged MCF7 cells bearing wild-type, Y537S, or D538G ERα were injected into the mammary ducts of NSG mice (MIND model), which were subsequently treated with lasofoxifene or fulvestrant as single agents or in combination with palbociclib. Tumor growth and metastasis were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis.ResultsAs a monotherapy, lasofoxifene was more effective than fulvestrant at inhibiting primary tumor growth and reducing metastases. Adding palbociclib improved the effectiveness of both lasofoxifene and fulvestrant for tumor suppression and metastasis prevention at four distal sites (lung, liver, bone, and brain), with the combination of lasofoxifene/palbociclib being generally more potent than that of fulvestrant/palbociclib. X-ray crystallography of the ERα ligand binding domain (LBD) shows that lasofoxifene stabilizes an antagonist conformation of both wild-type and Y537S LBD. The ability of lasofoxifene to promote an antagonist conformation of Y537S, combined with its long half-life and bioavailability, likely contributes to the observed potent inhibition of primary tumor growth and metastasis of MCF7 Y537S cells.ConclusionsWe report for the first time the anti-tumor activity of lasofoxifene in mouse models of endocrine therapy-resistant breast cancer. The results demonstrate the potential of using lasofoxifene as an effective therapy for women with advanced or metastatic ER+ breast cancers expressing the most common constitutively active ERα mutations.

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KISS1 in metastatic cancer research and treatment: potential and paradoxes.

Publications

KISS1 in metastatic cancer research and treatment: potential and paradoxes.

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