Hence, using clinical specimens as well as in vivo models, we found that the expression of CALML5 might be the potential risk factor in the treatment of HER2+HR+ breast cancer and the introduction of dalpiciclib could abrogate the drug resistance to pyrotinib + tamoxifen in HER2+HR+ breast cancer due to the expression of CALML5. This evidence concerns the gene CALML5 and breast cancer.