Melatonin inhibits estrogen production in ERα+ breast cancer associated fibroblasts and counteracts tamoxifen resistance
Introduction: Approximately 12.4% of women will develop breast cancer during their lifetime. Furthermore, 70% of all breast cancers are known to be caused by increased receptor-estrogen interaction (ER+). Studies have hypothesized that the proliferation promoting estrogen is produced by breast adipose fibroblasts (BAF) in postmenopausal women, the cohort with the highest rate of breast cancer. Further research highlights hyperestrogenism to be related to disruption of the body’s circadian rhythm, specifically the oncostatic hormone, melatonin. The presence of MLT is significant as it downregulates the CYP19A1 gene, which codes for the aromatase P450 enzyme responsible for converting circulating steroids to estrogen. Exposure to light at night (dLEN) lowers MLT levels leading to a tendency to develop breast cancer. In addition, dLEN has been proposed to cause resistance to anti-estrogenic chemotherapy compounds such as tamoxifen. Methods: Fibroblasts were isolated from cancer free and Invasive Ductal Carcinoma patients. CYP19A1 transcription was promoted using prostaglandin E2. Levels of melatonin G-protein coupled receptors were assessed in the fibroblasts using PCR. Then specific concentrations (10 μM, 1 nM, 10 pM) of MLT were added to treat the fibroblasts. To investigate the role of MLT in re-establishing sensitivity to chemotherapeutic drugs, rats were implanted with tumors from Er+ MCF-7 human breast cancer cell lines. Arterial blood was collected to determine melatonin and tumor metabolic markers. Results: Each concentration of MLT administered showed decreased activation of CYP19A1 compared to the vehicle (51%- 10 pM, 28%- 1 nM, 35%- 10 μM). Furthermore, to assess the the production of estrogen, aromatase activity was observed, which was significantly decreased following PGE2 and MLT administration, compared to PGE stimulation alone(p< .001). dLEN conditions reduced latency-to-onset of developing tumors (p<.001). dLEN+tamoxifen rats showed complete resistance to the drug, while Tumor xenografts from dLEN+ melatonin+tamoxifen rats showed dramatic regression(P< .0001). Conclusions: MLT exerts inhibitory and modulatory effects on estrogen sensitive breast cancers. One of these effects include inhibition of aromatase activity in the production of estrogen in breast adipose fibroblasts in postmenopausal women.3 Dauchy et al. also established the importance of MLT in retaining sensitivity to tamoxifen therapy. The implications of these findings are significant, as resistance to endocrine therapies range from 30-50% in ERα+ patients. and MLT may provide a non-toxic antagonistic approach to the treatment of breast cancer.[6,7].
- SEER Cancer Stat Facts: Female Breast Cancer. National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/statfacts/html/breast.html
- Lumachi, F., et al. “Treatment of estrogen receptor-positive breast cancer.” Current medicinal chemistry 20.5 (2013): 596-604.
- Knower, Kevin C., et al. “Melatonin suppresses aromatase expression and activity in breast cancer associated fibroblasts.” Breast cancer research and treatment 132.2 (2012): 765-771.
- Nooshinfar, Elaheh, et al. “Melatonin, an inhibitory agent in breast cancer.” Breast Cancer 24.1 (2017): 42-51.
- Dauchy, Robert T., et al. “Circadian and melatonin disruption by exposure to light at night drives intrinsic resistance to tamoxifen therapy in breast cancer.” Cancer research 74.15 (2014): 4099-4110.
- Alonso-González, Carolina, et al. “Melatonin enhancement of the radiosensitivity of human breast cancer cells is associated with the modulation of proteins involved in estrogen biosynthesis.” Cancer letters 370.1 (2016): 145-152.
- Xiang, Shulin, et al. “Doxorubicin resistance in breast cancer is driven by light at night-induced disruption of the circadian melatonin signal.” Journal of pineal research 59.1 (2015): 60-69.