studies also found that MHT use was associated with elevated risk of ER+ breast cancer 8–12 . The biological mechanisms underlying the effect of MHT use on breast cancer risk is not fully understood. One proposed mechanism is that higher estrogen and progesterone levels increase the proliferation of breast
epithelial cells, which results in accumulation of genetic mutations and insufficient DNA repair13,14, and therefore induces mutagenesis 15,16 . Genome-wide association studies (GWAS) have identified over 200 single nucleotide polymorphisms (SNPs) that are associated with invasive breast cancer risk 17–19 . Further analyses based on these GWAS findings have identified several genes that might interact with MHT use on breast cancer risk, including
SNPs regulating the fibroblast growth factor receptor two (FGFR2) gene 20 , as well as SNPs close to the Kruppel like factor 4 (KLF4) gene and the insulin like growth-factor-binding protein 5 (IGFBP5) gene 21–23 . A meta-analysis of four genome-wide case-only interaction studies found suggestive evidence of interactions between MHT use and SNPs in genes related to transmembrane signaling and immune cell activation 24 . However, none of the findings reached genome-wide significance.
In the present study, we performed a comprehensive genome-wide interaction analysis of current MHT use by pooling individual-level data from 26 epidemiological studies. We also performed genome-wide interaction analysis of MHT use on ER+ breast cancer specifically