The Mechanism Of Palbociclib Inhibiting Synergistically With Lapatinib Or Herceptin In The Proliferation Of Breast Cancer Stem Cells

Study shows that the cancer stem cells（CSCs）of MCF-7,which is a cell line of Luminal breast cancer with Her2（-）,also selectively expresses Her2,and Herceptin（H）is effective to it^[1].What’s more,the combination of drug P and H inhibits synergistically to BT-474,which is Luminal breast cancer with Her2（+）^[2].It is well-known that CSCs is a crucial role in drug resistance,recurrence and metastasis of tumors.Therefore,we assume that if drug P inhibits synergistically with drug H or Lapatinib（L）,which is EGFR inhibitor,to the CSCs of Luminal breast cancer,and study the related mechanism.First of all,we detect the expression of ALDH and CD44+/CD24-of breast cancer cell lines and 3 sample of breast cancer,which are Luminal with Her2 negative,TNBC and Her2（+）subtypes.The result shows that TNBC expresses ALDH and CD44+/CD24-the most in the cell lines,while T-47D,which is Luminal with Her2（-）,expresses the least.But to the 3 breast cancer samples,the highest expression of CD44+/CD24-is Her2（+）subtype,and the lowest expression is the TNBC subtype.Then,we observe the effect of the combinations of drugs to Luminal breast cancer stem cells by MFE,the cytoskeleton,the roughness of the cells’surface and apoptosis,which shows that the combinations of P+L and P+H have stronger capability of inhibiting the MFE,destroying the structure of the cytoskeleton and increasing the roughness of the cells’surface of the CSCs of MCF-7 and Her2-18.But the combinations have little effect to the apoptosis compared with single drug.Thus,we explore the related mechanism by cell circle,the phosphorylation of proteins in related signal passways and the mitochondrial function.We find out that the combinations of drugs increase the G1 arrest of the cell circle much more stronger,decrease the phosphorylation of p-S6K1,p-RB and p-S6RP in the pathway of AKT/m TOR and cyclin D1/CDK4,as well as the ATP production,maximal respiration,non-mitochondrial respiration and OCR in the mitochondrial function of the CSCs of Her2-18.The results receal the effect of the combinations of P+L and P+H.It provides a new therapeutic strategy for Luminal breast cancer,which has important clinical significance.