Adam Hauch

Melatonin: an inhibitor of breast cancer

The present review discusses recent work on melatonin-mediated circadian regulation, the metabolic and molecular signaling mechanisms that are involved in human breast cancer growth, and the associated consequences of circadian disruption by exposure to light at night (LEN). The anti-cancer actions of the circadian melatonin signal in human breast cancer cell lines and xenografts heavily involve MT1 receptor-mediated mechanisms. In estrogen receptor alpha (ERα)-positive human breast cancer, melatonin suppresses ERα mRNA expression and ERα transcriptional activity via the MT1 receptor. Melatonin also regulates the transactivation of other members of the nuclear receptor superfamily, estrogen-metabolizing enzymes, and the expression of core clock and clock-related genes. Furthermore, melatonin also suppresses tumor aerobic metabolism (the Warburg effect) and, subsequently, cell-signaling pathways critical to cell proliferation, cell survival, metastasis, and drug resistance. Melatonin demonstrates both cytostatic and cytotoxic activity in breast cancer cells that appears to be cell type-specific. Melatonin also possesses anti-invasive/anti-metastatic actions that involve multiple pathways, including inhibition of p38 MAPK and repression of epithelial-mesenchymal transition (EMT). Studies have demonstrated that melatonin promotes genomic stability by inhibiting the expression of LINE-1 retrotransposons. Finally, research in animal and human models has indicated that LEN-induced disruption of the circadian nocturnal melatonin signal promotes the growth, metabolism, and signaling of human breast cancer and drives breast tumors to endocrine and chemotherapeutic resistance. These data provide the strongest understanding and support of the mechanisms that underpin the epidemiologic demonstration of elevated breast cancer risk in night-shift workers and other individuals who are increasingly exposed to LEN.

Circadian and Melatonin Disruption by Exposure to Light at Night Drives Intrinsic Resistance to Tamoxifen Therapy in Breast Cancer

Resistance to endocrine therapy is a major impediment to successful treatment of breast cancer. Preclinical and clinical evidence links resistance to antiestrogen drugs in breast cancer cells with the overexpression and/or activation of various pro-oncogenic tyrosine kinases. Disruption of circadian rhythms by night shift work or disturbed sleep-wake cycles may lead to an increased risk of breast cancer and other diseases. Moreover, light exposure at night (LEN) suppresses the nocturnal production of melatonin that inhibits breast cancer growth. In this study, we used a rat model of estrogen receptor (ERα(+)) MCF-7 tumor xenografts to demonstrate how altering light/dark cycles with dim LEN (dLEN) speed the development of breast tumors, increasing their metabolism and growth and conferring an intrinsic resistance to tamoxifen therapy. These characteristics were not observed in animals in which the circadian melatonin rhythm was not disrupted, or in animals subjected to dLEN if they received nocturnal melatonin replacement. Strikingly, our results also showed that melatonin acted both as a tumor metabolic inhibitor and a circadian-regulated kinase inhibitor to reestablish the sensitivity of breast tumors to tamoxifen and tumor regression. Together, our findings show how dLEN-mediated disturbances in nocturnal melatonin production can render tumors insensitive to tamoxifen.

Doxorubicin Resistance in Breast Cancer is Driven by Light at Night Induced Disruption of the Circadian Melatonin Signal

Chemotherapeutic resistance, particularly to doxorubicin (Dox), represents a major impediment to successfully treating breast cancer and is linked to elevated tumor metabolism and tumor over‐expression and/or activation of various families of receptor‐ and non‐receptor‐associated tyrosine kinases. Disruption of circadian time structure and suppression of nocturnal melatonin production by dim light exposure at night (dLEN), as occurs with shift work, and/or disturbed sleep–wake cycles, is associated with a significantly increased risk of an array of diseases, including breast cancer. Melatonin inhibits human breast cancer growth via mechanisms that include the suppression of tumor metabolism and inhibition of expression or phospho‐activation of the receptor kinases AKT and ERK1/2 and various other kinases and transcription factors. We demonstrate in tissue‐isolated estrogen receptor alpha‐positive (ERα+) MCF‐7 human breast cancer xenografts, grown in nude rats maintained on a light/dark cycle of LD 12:12 in which dLEN is present during the dark phase (suppressed endogenous nocturnal melatonin), a significant shortening of tumor latency‐to‐onset, increased tumor metabolism and growth, and complete intrinsic resistance to Dox therapy. Conversely, a LD 12:12 dLEN environment incorporating nocturnal melatonin replacement resulted in significantly lengthened tumor latency‐to‐onset, tumor regression, suppression of nighttime tumor metabolism, and kinase and transcription factor phosphorylation, while Dox sensitivity was completely restored. Melatonin acts as both a tumor metabolic inhibitor and circadian‐regulated kinase inhibitor to reestablish the sensitivity of breast tumors to Dox and drive tumor regression, indicating that dLEN‐induced circadian disruption of nocturnal melatonin production contributes to a complete loss of tumor sensitivity to Dox chemotherapy.

Melatonin suppression of aerobic glycolysis (Warburg effect), survival signalling and metastasis in human leiomyosarcoma

Leiomyosarcoma (LMS) represents a highly malignant, rare soft tissue sarcoma with high rates of morbidity and mortality. Previously, we demonstrated that tissue‐isolated human LMS xenografts perfused in situ are highly sensitive to the direct anticancer effects of physiological nocturnal blood levels of melatonin which inhibited tumour cell proliferative activity, linoleic acid (LA) uptake and metabolism to 13‐hydroxyoctadecadienoic acid (13‐HODE). Here, we show the effects of low pharmacological blood concentrations of melatonin following oral ingestion of a melatonin supplement by healthy adult human female subjects on tumour proliferative activity, aerobic glycolysis (Warburg effect) and LA metabolic signalling in tissue‐isolated LMS xenografts perfused in situ with this blood. Melatonin markedly suppressed aerobic glycolysis and induced a complete inhibition of tumour LA uptake, 13‐HODE release, as well as significant reductions in tumour cAMP levels, DNA content and [3H]‐thymidine incorporation into DNA. Furthermore, melatonin completely suppressed the phospho‐activation of ERK 1/2, AKT, GSK3β and NF‐kB (p65). The addition of S20928, a nonselective melatonin antagonist, reversed these melatonin inhibitory effects. Moreover, in in vitro cell culture studies, physiological concentrations of melatonin repressed cell proliferation and cell invasion. These results demonstrate that nocturnal melatonin directly inhibited tumour growth and invasion of human LMS via suppression of the Warburg effect, LA uptake and other related signalling mechanisms. An understanding of these novel signalling pathway(s) and their association with aerobic glycolysis and LA metabolism in human LMS may lead to new circadian‐based therapies for the prevention and treatment of LMS and potentially other mesenchymally derived solid tumours.

Association of Surgeon Volume With Outcomes and Cost Savings Following Thyroidectomy: A National Forecast

IMPORTANCE Incidence of thyroidectomies is continuing to increase. Identifying factors associated with favorable outcomes can lead to cost savings. OBJECTIVE To assess the association of surgeon volume with clinical outcomes and costs of thyroidectomy. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional analysis performed in October of 2014 of adult (≥ 18 years) inpatients in US community hospitals using the Nationwide Inpatient Sample for the years 2003 through 2009. EXPOSURES Thyroidectomy. MAIN OUTCOMES AND MEASURES Complications, length of stay, and cost following thyroidectomy in relation to surgeon volume. Surgeon volumes were stratified into low (1-3 thyroidectomies per year), intermediate (4-29 thyroidectomies per year), and high (≥ 30 thyroidectomies per year). RESULTS A total of 77,863 patients were included. Procedures performed by low-volume surgeons were associated with a higher risk of postoperative complications compared with high-volume surgeons (15.8% vs 7.7%; OR, 1.55 [95% CI, 1.19-2.03]; P = .001). Mean (SD) hospital cost was significantly associated with surgeon volume (high volume,

Association of Socioeconomic Status, Race, and Ethnicity With Outcomes of Patients Undergoing Thyroid Surgery

6662.69 [

The safety and efficacy of approaches to liver resection: a meta-analysis.

409.31]; intermediate volume,

Molecular deficiency (ies) in MT1 melatonin signaling pathway underlies the melatonin‐unresponsive phenotype in MDA‐MB‐231 human breast cancer cells

6912.41 [

Robot-Assisted Versus Standard Laparoscopic Colorectal Surgery

137.20]; low volume,

Robotic versus laparoscopic colorectal surgery.

10,396.21 [