Effects of physiological deficits in pineal melatonin on Triple Negative Breast Cancer

Abstract

Background: Triple negative breast cancer (TNBC) is aggressive and treatment resistant. Evidence suggests that deficits in melatonin signaling increase TNBC risk: conditions that suppress melatonin increased incidence, low melatonin receptor expression correlates with worse prognosis, and high-dose melatonin can inhibit TNBC. Together this suggests that normalizing pineal melatonin could reduce TNBC incidence and/or mortality. The goal of this study was to determine whether small physiological deficits in melatonin alone, can increase risk for TNBC, and how 'normal' melatonin would be protective. Methods: The effect of melatonin treatment on 4t1 cells in vitro was measured using the MTT cell viability assay, and gene expression of breast cancer and melatonin signaling markers. The effect of pineal gland status on 4t1 cell allografts was tested in C3Sn mice (Mus Musculus) with either an intact pineal (control) or surgical removal of the pineal causing a ~50% deficit in plasma melatonin. Orthotopic tumors were assessed by histopathology and metastasis by strain specific qPCR against 4t1 cell and host gDNA. Results: Melatonin treatment induced significant changes in gene expression, with a significant reduction in derived PAM50 Risk of Recurrence score (ROR in Not treated = 65.5 ± 10.6 Mean SEM; Treated with 25pg/ml of melatonin 20.8 ± 8.3; P = 0.008), suggesting melatonin treatment would improve prognosis. A ~50% reduction in plasma melatonin increased orthotopic tumors, but this was non-significant, and had no effect on metastasis from tail vein allograft. Conclusions: Physiological deficits in melatonin do alter the oncogenic status of 4t1 tumor cells but this has only a limited effect on growth and metastasis in vivo. Lack of significance in orthotopic tumor formation may be due to small sample size, and it is possible that any protective effect of melatonin occurs earlier in tumor development than we have tested.

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