Breast cancer risk-associated SNPs in the mTOR promoter form de novo KLF5 and ZEB1 binding sites that influence the cellular response to paclitaxel

ZEB1 (a positive enhancer) and KLF5 (a negative silencer) affect transcription factors and play inherently conserved roles in tumorigenesis and multidrug resistance. In humans, the rs2295080T-allele at the mTOR promoter locus has been associated with human cancer risk; however, the 63 bp spacing of another SNP rs2295079 has not been identified. Here, we discovered, for the first time, that rs2295079 (-78C/G) and rs2295080 (-141G/T) formed linkage haplotypes, with Ht1 (-78C/-141G) and Ht2 (-78G/-141T) being dominant, which were associated with distinct susceptibility to breast cancer, response to paclitaxel (PTX) and clinical outcomes in breast cancer. At the cellular level, compared to Ht1, Ht2 exhibits a much stronger effect on promoting mTOR expression, leading to enhanced tumor cell growth and strengthened resistance to PTX treatment. Mechanistically, the -141T allele of Ht2 creates a novel ZEB1 binding site; meanwhile, the -78C allele of Ht1 exists as an emerging KLF5 binding site, which synergistically induces promote/inhibit mTOR expression, cell proliferation and excretion of cytotoxic drugs through the ZEB1/KLF5-mTOR-CCND1/ABCB1 cascade, thereby affecting the response to PTX treatment in vivo and in vitro. Our results suggest the existence of a ZEB1/KLF5-mTOR-CCND1/ABCB1 axis in human cells that could be involved in PTX response pathways and functionally regulate inter-individualized breast cancer susceptibility and prognosis. Implications: The current study highlights the function of haplotypes of mTOR -78C/-141G and -78G/-141T, in affecting breast cancer susceptibility and PTX response regulated by ZEB1/KLF5-mTOR-CCND1/ABCB1 axis.