This review discusses recent work on melatonin-mediated circadian regulation and metabolic and molecular signaling mechanisms involved in human breast cancer growth and 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, via the MT1 receptor, suppresses ERα mRNA expression and ERα transcriptional activity. As well, melatonin regulates the transactivation of other members of the nuclear receptor super-family, estrogen metabolizing enzymes, and the expression of core clock and clock-related genes. Furthermore, melatonin also suppresses tumor aerobic metabolism (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-to-mesenchymal transition. Studies demonstrate that melatonin promotes genomic stability by inhibiting the expression of LINE-1 retrotransposons. Finally, research in animal and human models indicate that LEN induced disruption of the circadian nocturnal melatonin signal promotes the growth, metabolism, and signaling of human breast cancer to drive breast tumors to endocrine and chemotherapeutic resistance. These data provide the strongest understanding and support of the mechanisms underpinning the epidemiologic demonstration of elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LEN.

The importance of the circadian/melatonin signal in suppressing the metastatic progression of breast and other cancers has been reported by numerous laboratories including our own. Currently, the mechanisms underlying the anti-metastatic actions of melatonin have not been well established. In the present study, the anti-metastatic actions of melatonin were evaluated and compared on the ERα-negative, Her2-positive SKBR-3 breast tumor cell line and ERα-positive MCF-7 cells overexpressing a constitutively active HER2.1 construct (MCF-7Her2.1 cells). Activation of Her2 is reported to induce the expression and/or phosphorylation-dependent activation of numerous kinases and transcription factors that drive drug resistance and metastasis in breast cancer. A key signaling node activated by the Her2/Mapk/Erk pathway is Rsk2, which has been shown to induce numerous signaling pathways associated with the development of epithelial-to-mesenchymal transition (EMT) and metastasis including: Creb, Stat3, cSrc, Fak, Pax, Fascin, and actin polymerization. The data demonstrate that melatonin (both endogenous and exogenous) significantly represses this invasive/metastatic phenotype through a mechanism that involves the suppression of EMT, either by promoting mesenchymal-to-epithelial transition (MET), and/or by inhibiting key signaling pathways involved in later stages of metastasis. These data, combined with our earlier in vitro studies, support the concept that maintenance of elevated and extended duration of nocturnal melatonin levels plays a critical role in repressing the metastatic progression of breast cancer.

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Resistance to chemotherapy is a significant impediment to the treatment of breast cancer. More than 30% of breast cancer patients present with intrinsic resistance to chemotherapy; almost all who initially respond will develop acquired resistance. Resistant tumors frequently exhibit constitutive activation of numerous survival signaling pathways, including ERK, AKT, NF-kB, and STAT3. We have reported that the circadian hormone melatonin inhibits the growth of both ERá+/ERá- breast cancers and, as well as the daytime induced phospho-activation of ERK1/2, AKT and NF-kB in breast tumor xenografts. We also demonstrated that dim light at night (dLAN), by decreasing nocturnal melatonin, resulted in constitutive phospho-activation of ERK1/2, CREB, NF-kB, and STAT3, promoting resistance to tamoxifen and doxorubicin therapy. Here we tested the hypothesis that dLAN, via phospho-activation of ERK1/2 and STAT3, promotes resistance to paclitaxel (Pax). Female nude rats with “tissue-isolated” MCF-7 breast cancer xenografts were housed in photoperiodic conditions of either LD 12:12, 12:12dLAN (0.2 lux), or 12:12dLAN supplemented with nighttime melatonin (0.05 õg/ml) in the drinking water, with lights on at 0600 hrs and off at 1800 hrs. When estimated tumor weights reached 2.5 g, animals were treated daily with either diluent or Pax i.p. (4õã/kg) 2 h prior to onset of dLAN or dLAN with nighttime melatonin supplementation. Blood samples collected during the mid-dark phase (2400 hrs) showed elevated nocturnal melatonin in the LD 12:12 group, but significantly suppressed melatonin in the dLAN group. Tumor xenografts from rats housed in dLAN showed a 3-fold decrease in latency-to-onset and a 2.8-fold increased growth rates vs. those from rats receiving melatonin supplementation. Tumor cAMP levels, linoleic acid, and tumor metabolism (Warburg effect) were significantly elevated in dLAN tumors. Numerous signaling pathways including ERK1/2, RSK2, and STAT3, were phospho-activated and others including AKT and HER2/3 were elevated at 2400 hrs by dLAN but repressed in dLAN melatonin supplemented tumors. Tumors from dLAN rats showed intrinsic resistance to Pax, whereas those in LD 12:12 or dLAN and supplemented with nighttime melatonin rapidly regressed. These findings show that temporally coordinated and integrated metabolic and signal transduction mechanisms, particularly the STAT3 pathway, underlying human breast cancer growth, can be activated by the host's exposure to LAN with profound effects culminating in rapid tumor progression and the development of resistance to chemotherapy. Citation Format: Steven M. Hill, Shulin Xiang, Robert T. Dauchy, Lulu mao, Lin Yuan, Adam Hauch, Victoria P. Belancio, Melissa A. Wren-Dail, David Pointer, Peter W. Lundberg, Whitney M. Summers, David E. Blask. Circadian/melatonin disruption by dim light at night drives paclitaxel resistance in breast cancer via activation of stat3. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 874.