miR-484 suppresses endocrine therapy-resistant cells by inhibiting KLF4-induced cancer stem cells in estrogen receptor-p
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ORIGINAL ARTICLE
miR‑484 suppresses endocrine therapy‑resistant cells by inhibiting KLF4‑induced cancer stem cells in estrogen receptor‑positive cancers Yulei Wei1 · Hong Li1 · Quanxin Qu1 Received: 27 March 2020 / Accepted: 7 August 2020 © The Japanese Breast Cancer Society 2020
Abstract 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. Keywords miR-484 · Kruppel-like factor 4 · Cancer stem cell · Breast cancer · Endocrine therapy
Introduction Estrogens are the primary female sex hormones, which are crucial for the development of the reproductive system, as well as cancer progression in estrogen-dependent organs, such as the breast, ovaries and uterus. Estrogens exert their effects via binding to estrogen receptor (ER), which belongs to the nuclear steroid receptor superfamily. After being activated by estrogens, ER acts as a nuclear transcription factor via binding to the genomic promoters/enhancers of its target genes to regulate gene transcriptional activity. There are two isoforms of ER, ERα and ERβ, encoded by the ESR1 and ESR2 genes, respectively. ERα is more important in the breast, while ERβ is more important for the development of the female reproductive organs, such as the ovaries [1]. Breast cancer (BCa), which may be hereditary and strongly affected by age and estrogen status in women, is the most frequently diagnosed cancer and the second cause of cancer-related mortality among women in western countries * Quanxin Qu [email protected] 1
Department of Gynecology and Obstetrics, Tianjin First Central Hospital, 24 Fukang Road, Nankai District, Tianjin 300192, People’s Republic of China
[2]. Approximately 70% of BCas are ER-positive. Due to the critical roles of ER signaling in BCa [3], endocrine therapy (mainly tamoxifen) that targets the ER pathway is the mainstay of treatment in ER-positive breast cancers. Initially, endocrine therapy (mainly anti-estrogen therapy) significantly decreases disease recurrence and cancer-related mortality. However, resistance to endocrine therapy develops in at least one-third of the patients [4]. Ovaria
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