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. 2018 May 4;9:219. doi: 10.3389/fendo.2018.00219

Figure 1.

Figure 1

Cross talk between E2–estrogen receptor-α (ERα) signaling pathways and circadian rhythms in breast cancer. Two of the four estrogen signaling pathways involve E2 stimulation and are shown here (65). In the classical genomic pathway, E2-bound estrogen receptor (ER) (either ERα or ERβ) dimerizes, changes conformation, translocates to the nucleus, and binds to the estrogen response elements (EREs). After binding to the EREs, the E2–ER complex recruits other co-activators, including Circadian Locomotor Output Cycles Kaput (CLOCK) and possibly brain and muscle Arnt-like protein 1 (BMAL1) (74), to initiate the transcription of target genes. CLOCK overexpression in breast tumors and promotion of tumor cell proliferation may be caused by co-activation with E2–ER complexes (77, 78). In the non-genomic pathway, E2–ERα complexes accumulate near the membrane and then recruit protein kinases [Src and phosphoinositide 3-kinase (PI3K)] to activate signaling cascades (Akt and Ras/MAPK). BMAL1 has been shown to suppress the Akt/MMP2 pathway and further inhibit cancer cell invasion (79). BMAL1 can suppress cancers, and its expression is downregulated or disrupted in various breast cancer cell lines (67, 80–83). By contrast, REV-ERBβ (a repressor in the secondary transcriptional/translational feedback loop) is generally overexpressed in breast tumor samples; its protective function can allow cancer cells to develop chemotherapy resistance (84). PER2 is a direct ERα target gene and can bind to ERα and cause its degradation. In ERα-positive breast cancer cells, both PER2 and ERα lose their circadian oscillations, the underlying mechanism of which is not well understood. The cancer suppressor p53 can directly bind to the PER2 promoter and inhibit its transcriptional activity (85). E2–ER complexes can block the induction of proapoptotic p53 target genes by binding to p53 protein in ER-positive breast cancer cells, thus helping cancer cells avoid apoptosis (73). Re-introduction of PER2 into the ER-positive breast cancer cells can induce p53 expression (72). Abbreviations: TF, transcriptional factor; RE, response element; E2, 17 β-estradiol.