miR-484 suppresses endocrine therapy-resistant cells by inhibiting KLF4-induced cancer stem cells in estrogen receptor-positive cancers.

Endocrine therapy (mainly anti-estrogen therapy) is the mainstay of treatment for estrogen receptor (ER) positive breast cancer (BCa). However, approximately one-third of BCa patients who receive endocrine therapy may develop resistance. The detailed mechanism is still unclear. MCF7 and T-47D cells were treated with ERα antagonist tamoxifen for 2 months until they became tamoxifen-resistant. qPCR was used to detect the stem markers like CD44, OCT4 and SOX2. Flow cytometry and sphere formation were performed to test the stemness. Cell growth and invasiveness were measured by MTS assay, xenograft mouse model, and invasion assay. We found that tamoxifen resistant BCa cells acquired certain malignant phenotypes, such as higher expression of KLF4, stemness and enhanced invasiveness. Furthermore, miR-484 was found to act as a tumor suppressor and directly downregulated KLF4. KLF4-induced cancer stem cell (CSCs) contributes to anti-ER therapy resistant and is a potential target in endocrine therapy-resistant cancers.