A truncated Ah receptor blocks the hypoxia and estrogen receptor signaling pathways: A viable approach for breast cancer treatment

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor which requires heterodimerization with the Ah receptor nuclear translocator (Arnt) for function. Arnt is also a dimerization partner of the hypoxia inducible factor la (HIF-1 alpha) for the hypoxia signaling. Additionally, Arnt is found to be a potent coactivator of the estrogen receptor (ER) signaling. Thus we examined whether the presence of an increased amount of AhR may suppress both the HIF-1 alpha. and ER signaling pathways by sequestering Arnt. We tested our hypothesis using a human AhR construct C Delta 553 which is capable of heterodimerizing with Arnt in the absence of a ligand. Transient transfection studies using a corresponding luciferase reporter plasmid in MCF-7 cells showed that CA553 effectively suppressed the AhR, HIF-1a, and ER signaling pathways. Reverse transcription/real-time QPCR data showed that CA553 blocked the up-regulation of the target genes controlled by AhR (CYP1A1), HIF-1 alpha. (VEGF, aldolase C, and LDH-A), and ER (GREB1, pS2, and c-myc) in MCF-7 cells. Since both HIF-1 alpha and ER are highly active in the ER-positive breast cancer, CA553 has the potential to be developed as a protein drug to treat breast cancer by blocking these two signaling pathways.