Lapatinib Reverses ER-α36-associated Tamoxifen Resistance In Breast Cancer Cells

Objective:Studies have suggested ER-a36can make hormone receptor-positive breast cancer resistance to endocrine therapy by the non-classic estrogen signaling. Lapatinib is a kind of small molecule epidermal growth factor tyrosine kinase inhibitor, can be adjusted by blocking signals inhibit breast cancer cell proliferation. This study will explore whether Lapatinib can reverse tamoxifen-resistance in hormone receptor-positive breast cancer cells by down regulation ER-a36related signaling, and preliminary explore its molecular mechanism. Provides new theoretical support for endocrine therapy and targeted therapy in breast cancer.Methods:Use techniques of MTT, AnnexinV-FITC/PI double staining flow cytometry and Western Blot to detect breast cancer cell’s cell proliferation cycle, cell apoptosis, and the related changes of protein levels conducted by Lapatinib alone or Lapatinib with4-hydroxy-tamoxifen (4-OHT) Results:(1) The results of MTT show Lapatinib obviously inhibit proliferation of breast cancer cell. There’s dose-dependent in MCF-7, MCF-7/ER-α36cells.(2) The result of AnnexinV-FITC/PI double staining flow cytometry shows that Lapatinib can significantly enhance the apoptosis induced by4-OHT in MCF-7/ER-α36cells(P<0.001).(3) Pretreatment by Lapatinib or association with4-OHT all can enhance activation of the Caspase family protein in the beginning and executing phase in apoptosis, and inhibit the expression of anti-apoptotic Bcl-2protein. Reduce the positive regulated proteins in cell cycle, such as Cyclin D1, Cyclin D3and CDK2, CDK4, et al; Lapatinib significantly inhibit Akt T308loci and the phosphorylation active of S6K1protein, increasing sensitivity and partly reversing the effect of4-OHT in MCF-7/ER-a36.Conclusion:Lapatinib can reverse the effect of tamoxifen-resistance in ER-a36overexpression hormone receptor positive breast cancer cells. The mechanism is mainly related to:(1) Induce cell to apoptosis and stasis;(2) Inhibit the over activation of ER-a36related non-classic Akt-mTOR signaling pathways. Lapatinib may be the new target for therapy ER-a36overexpression and TAM resistance breast cancer.