Abstract
Although endocrine therapies targeting estrogen receptor α (ERα) are effective in managing ER positive (+) breast cancer, many patients have primary resistance or develop resistance to endocrine therapies. In addition, ER+ breast cancer with PIK3CA activating mutations and 11q13-14 amplification have poor survival with unclear mechanism. We uncovered that higher expression of deubiquitinase USP35, located in 11q14.1, was associated with ER+ breast cancer and poor survival. Estrogen enhanced USP35 protein levels by downregulating USP35-targeting miRNA-140-3p and miRNA-26a-5p. USP35 promoted the growth of ER+ breast cancer in vitro and in vivo, and reduced the sensitivity of ER+ breast cancer cells to endocrine therapies such as tamoxifen and fulvestrant. Mechanistically, USP35 enhanced ERα stability by interacting and deubiquitinating ERα, and transcriptional activity of ERα by interacting with ERα in DNA regions containing estrogen response element. In addition, AKT, a key effector of PI3K, phosphorylated USP35 at Serine613, which promoted USP35 nuclear translocation, ERα transcriptional activity, and the growth of ER+ breast cancer cells. Our data indicate that USP35 and ERα form a positive feedback loop in promoting the growth of ER+ breast cancer. USP35 may be a treatment target for ER+ breast cancer with endocrine resistance or with PIK3CA mutations or hyperactivation of the PI3K pathway.
Highlights
Up to 70% of breast cancer is driven by estrogen receptor α (ERα) [1]
Ubiquitin Specific Peptidase 35 (USP35)-high expression was enriched in ESR1 up and luminal B up expression enhanced the growth of MCF-7 tumors compared with breast cancer (Fig. 1c). These observations were supported by vector control (Figs. 3e and 3f). These results indicate that USP35 immunohistochemistry analysis of USP35 in primary breast tumor acts as an oncogene in ER+ breast cancer
Akt phosphorylating Ser613 in USP35 is critical for USP35 nuclear translocation and enhancing ERα transcriptional activity (Fig. 7)
Summary
Up to 70% of breast cancer is driven by estrogen receptor α (ERα) [1]. Upon binding to estrogen, ERα translocates into the nucleus, binds DNA regions containing estrogen-responsive element (ERE), and regulates the transcription of a plethora of genes important for breast tumorigenesis [2, 3]. Isoform lacks the HEAT domain with an 5p mimic reduced USP35 protein levels in MCF-7 cells Another shorter form of USP35 (s-USP35) has been shown). A panels), were contransfected with miR-140-3p or miR-26a-5p mimics recent study revealed that USP35 is overexpressed in ovarian cancer into MCF-7 cells (Fig. 2d). USP35 promotes the growth of ER+ breast cancer in vitro and in vivo, expression by downregulating miR-26a-5p and miR-140-3p in ER+. USP35 nuclear translocation and promoting ERα transcriptional in vitro and in vivo activity and the growth of ER+ breast cancer cells.
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