Lower Beclin 1 downregulates HER2 expression to enhance tamoxifen sensitivity and predicts a favorable outcome for ER positive breast cancer.
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ABSTRACT:
SUBMITTER: Gu Y
PROVIDER: S-EPMC5581020 | biostudies-literature | 2017 Aug
REPOSITORIES: biostudies-literature
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Lower Beclin 1 downregulates HER2 expression to enhance tamoxifen sensitivity and predicts a favorable outcome for ER positive breast cancer.
Gu Yu Y Chen Tianxiang T Li Guangliang G Xu Cong C Xu Zhenzhen Z Zhang Jing J He Kuifeng K Zheng Linyan L Guan Zhonghai Z Su Xinyun X Cao Jiang J Teng Lisong L
Oncotarget 20160804 32
Tamoxifen(TAM) is one of the most effective endocrine treatment for estrogen receptor(ER)-positive breast cancer, however drug resistance greatly limits benefit of it. Our purpose is to uncover the role of Beclin 1 in tamoxifen resistance and prognosis of ER positive breast cancer. We established a tamoxifen resistant ER-positive breast cancer cell subline MCF-7R presenting with higher Beclin 1 and human epidermal growth factor receptor 2(HER2) levels than MCF-7. Silencing Beclin 1 decreased lev ...[more]
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Project description:Tamoxifen provided a successful treatment for ER-positive breast cancer for many years. However, HER2 overexpressing breast cancer cells respond poorly to tamoxifen therapy presumably by pass. The molecular mechanisms underlying development of tamoxifen resistance have not been well established. Recently, we reported that breast cancer cells with high levels of ER-?36, a variant of ER-?, were resistant to tamoxifen and knockdown of ER-?36 expression in tamoxifen resistant cells with the shRNA method restored tamoxifen sensitivity, indicating that gained ER-?36 expression is one of the underlying mechanisms of tamoxifen resistance. Here, we found that tamoxifen induced expression of ER-?36-EGFR/HER2 positive regulatory loops and tamoxifen resistant MCF7 cells (MCF7/TAM) expressed enhanced levels of the loops. Disruption of the ER-?36-EGFR/HER2 positive regulatory loops with the dual tyrosine kinase inhibitor Lapatinib or ER-?36 down-regulator Broussoflavonol B in tamoxifen resistant MCF7 cells restored tamoxifen sensitivity. In addition, we also found both Lapatinib and Broussoflavonol B increased the growth inhibitory activity of tamoxifen in tumorsphere cells derived from MCF7/TAM cells. Our results thus demonstrated that elevated expression of the ER-?36-EGFR/HER2 loops is one of the mechanisms by which ER-positive breast cancer cells escape tamoxifen therapy. Our results thus provided a rational to develop novel therapeutic approaches for tamoxifen resistant patients by targeting the ER-?36-EGFR/HER2 loops.
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Project description:Despite the clinical success of tamoxifen, its resistance remains a major challenge in breast cancer. Here we show that Aurora-A determines tamoxifen sensitivity by regulation of oestrogen receptor (ER)?. Ectopic expression of Aurora-A decreases and depletion of Aurora-A enhances tamoxifen sensitivity in ER?-positive breast cancer. Elevated Aurora-A was significantly associated with the recurrence of ER?-positive tumours. Notably, Aurora-A inhibitor MLN8237, which is currently in clinical trial, synergizes with tamoxifen and overcomes tamoxifen resistance. Furthermore, Aurora-A interacts with and phosphorylates ER? on serine-167 and -305, leading to increase in ER? DNA-binding and transcriptional activity. Elevated levels of Aurora-A are significantly associated with disease-free survival in ER?-positive but not ER?-negative breast cancers. These data suggest that Aurora-A has a pivotal role in tamoxifen resistance and ER? is a bona fide substrate of Aurora-A. Thus, Aurora-A represents a prognostic marker in ER?-positive tumour and a critical therapeutic target in tamoxifen-resistant breast cancer, and Aurora-A inhibitor could be used as either an independent or concurrent agent in tamoxifen-resistant tumour.
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Project description:IntroductionLymphocyte infiltration (LI) is often seen in breast cancer but its importance remains controversial. A positive correlation of human epidermal growth factor receptor 2 (HER2) amplification and LI has been described, which was associated with a more favorable outcome. However, specific lymphocytes might also promote tumor progression by shifting the cytokine milieu in the tumor.MethodsAffymetrix HG-U133A microarray data of 1,781 primary breast cancer samples from 12 datasets were included. The correlation of immune system-related metagenes with different immune cells, clinical parameters, and survival was analyzed.ResultsA large cluster of nearly 600 genes with functions in immune cells was consistently obtained in all datasets. Seven robust metagenes from this cluster can act as surrogate markers for the amount of different immune cell types in the breast cancer sample. An IgG metagene as a marker for B cells had no significant prognostic value. In contrast, a strong positive prognostic value for the T-cell surrogate marker (lymphocyte-specific kinase (LCK) metagene) was observed among all estrogen receptor (ER)-negative tumors and those ER-positive tumors with a HER2 overexpression. Moreover ER-negative tumors with high expression of both IgG and LCK metagenes seem to respond better to neoadjuvant chemotherapy.ConclusionsPrecise definitions of the specific subtypes of immune cells in the tumor can be accomplished from microarray data. These surrogate markers define subgroups of tumors with different prognosis. Importantly, all known prognostic gene signatures uniformly assign poor prognosis to all ER-negative tumors. In contrast, the LCK metagene actually separates the ER-negative group into better or worse prognosis.
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Project description:Tamoxifen (TAM) resistance is a major challenge in the treatment of estrogen receptor‑positive (ER+) breast cancer. To date, to the best of our knowledge, there are only a few studies available examining the response of patients with TAM‑resistant breast cancer to chemotherapy, and the guidelines do not specify recommended drugs for these patients. In the present study, TAM‑resistant cells were shown to exhibit increased proliferation and invasion compared with the parent cells, and the increased expression of c‑MYC was demonstrated to play an important role in TAM resistance. Furthermore, the TAM‑resistant cells were significantly more sensitive to cisplatin compared with the parent cells, and the silencing of c‑MYC expression desensitized the cells to cisplatin through the inhibition of the cell cycle. An increased c‑MYC expression was observed in 28 pairs of primary and metastatic tumors from patients treated with TAM, and the clinical remission rate of cisplatin‑based chemotherapy was significantly higher compared with other chemotherapy‑based regimens in 122 patients with TAM resistant breast cancer. Taken together, the data of the present study demonstrated that although c‑MYC was involved in TAM resistance, it increased the sensitivity of ER+ breast cancer to cisplatin. Thus, cisplatin may be a preferred chemotherapeutic agent for the treatment of patients with TAM‑resistant breast cancer, particularly in patients where the rapid control of disease progression is required.
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