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UCH-L1-mediated Down-regulation of Estrogen Receptor ? Contributes to Insensitivity to Endocrine Therapy for Breast Cancer.

ABSTRACT: Purpose: To determine the role of UCH-L1 in regulating ER? expression, and to evaluate whether therapeutic targeting of UCH-L1 can enhance the efficacy of anti-estrogen therapy against breast cancer with loss or reduction of ER?. Methods: Expressions of UCH-L1 and ER? were examined in breast cancer cells and patient specimens. The associations between UCH-L1 and ER?, therapeutic response and prognosis in breast cancer patients were analyzed using multiple databases. The molecular pathways by which UCH-L1 regulates ER? were analyzed using immunoblotting, qRT-PCR, immunoprecipitation, ubiquitination, luciferase and ChIP assays. The effects of UCH-L1 inhibition on the efficacy of tamoxifen in ER? (-) breast cancer cells were tested both in vivo and in vitro. Results: UCH-L1 expression was conversely correlated with ER? status in breast cancer, and the negative regulatory effect of UCH-L1 on ER? was mediated by the deubiquitinase-mediated stability of EGFR, which suppresses ER? transcription. High expression of UCH-L1 was associated with poor therapeutic response and prognosis in patients with breast cancer. Up-regulation of ER? caused by UCH-L1 inhibition could significantly enhance the efficacy of tamoxifen and fulvestrant in ER? (-) breast cancer both in vivo and in vitro. Conclusions: Our results reveal an important role of UCH-L1 in modulating ER? status and demonstrate the involvement of UCH-L1-EGFR signaling pathway, suggesting that UCH-L1 may serve as a novel adjuvant target for treatment of hormone therapy-insensitive breast cancers. Targeting UCH-L1 to sensitize ER negative breast cancer to anti-estrogen therapy might represent a new therapeutic strategy that warrants further exploration.

SUBMITTER: Chen XS

PROVIDER: S-EPMC6993235 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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UCH-L1-mediated Down-regulation of Estrogen Receptor α Contributes to Insensitivity to Endocrine Therapy for Breast Cancer.

Chen Xi-Sha XS Wang Kuan-Song KS Guo Wei W Li Lan-Ya LY Yu Pian P Sun Xin-Yuan XY Wang Hai-Yan HY Guan Yi-Di YD Tao Yong-Guang YG Ding Bo-Ni BN Yin Ming-Zhu MZ Ren Xing-Cong XC Zhang Yi Y Chen Ce-Shi CS Ye Yuan-Chao YC Yang Jin-Ming JM Cheng Yan Y

Theranostics 20200101 4

<b>Purpose</b>: To determine the role of UCH-L1 in regulating ERα expression, and to evaluate whether therapeutic targeting of UCH-L1 can enhance the efficacy of anti-estrogen therapy against breast cancer with loss or reduction of ERα. <b>Methods</b>: Expressions of UCH-L1 and ERα were examined in breast cancer cells and patient specimens. The associations between UCH-L1 and ERα, therapeutic response and prognosis in breast cancer patients were analyzed using multiple databases. The molecular p ...[more]

PMID: 32042339

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Project description:Aberrant activation of estrogen signaling through three ESR (estrogen receptor) subtypes, termed ESR1/ERα, ESR2/ERβ, and GPER1 (G protein-coupled estrogen receptor 1), is implicated in breast cancer pathogenesis and progression. Antiestrogens tamoxifen (TAM) and fulvestrant (FUL) are effective for treatment of ESR1-positive breast tumors, but development of resistance represents a major clinical challenge. However, the molecular mechanisms behind these events remain largely unknown. Here, we report that 17β-estradiol (E2), TAM, and FUL stabilize MORC2 (MORC family CW-type zinc finger 2), an emerging oncoprotein in human cancer, in a GPER1-dependent manner. Mechanistically, GPER1 activates PRKACA (protein kinase cAMP-activated catalytic subunit alpha), which in turn phosphorylates MORC2 at threonine 582 (T582). Phosphorylated MORC2 decreases its interaction with HSPA8 (heat shock protein family A [Hsp70] member 8) and LAMP2A (lysosomal associated membrane protein 2A), two core components of the chaperone-mediated autophagy (CMA) machinery, thus protecting MORC2 from lysosomal degradation by CMA. Functionally, knockdown of MORC2 attenuates E2-induced cell proliferation and enhances cellular sensitivity to TAM and FUL. Moreover, introduction of wild-type MORC2, but not its phosphorylation-lacking mutant (T582A), in MORC2-depleted cells restores resistance to antiestrogens. Clinically, the phosphorylation levels of MORC2 at T582 are elevated in breast tumors from patients undergoing recurrence after TAM treatment. Together, these findings delineate a phosphorylation-dependent mechanism for MORC2 stabilization in response to estrogen and antiestrogens via blocking CMA-mediated lysosomal degradation and uncover a dual role for MORC2 in both estrogen-induced proliferation and resistance to antiestrogen therapies of breast cancer cells.Abbreviations4-OHT: 4-hydroxytamoxifen; Baf A1: bafilomycin A1; CMA: chaperone-mediated autophagy; E2: 17β-estradiol; ESR: estrogen receptor; FUL: fulvestrant; GPER1: G protein-coupled estrogen receptor 1; HSPA8: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; MORC2: MORC family CW-type zinc finger 2; PRKACA: protein kinase cAMP-activated catalytic subunit alpha; TAM: tamoxifen; VCL: vinculin.

Project description:Despite the effectiveness of endocrine therapies in estrogen receptor positive (ER+) breast cancer, approximately 40% of patients relapse. Previously, we identified the Focal-adhesion kinase canonical pathway as a major contributor of resistance to estrogen deprivation and cellular-sarcoma kinase (c-src) as a dominant gene in this pathway. Dasatinib, a pan-src inhibitor, has recently been used in clinical trials to treat ER+ patients but has shown mixed success. In the following study, using isogenic cell line models, we provide a potential explanation for these findings and suggest a sub-group that may benefit. A panel of isogenic cell lines modelling resistance to aromatase inhibitors (LTED) and tamoxifen (TAMR) were assessed for response to dasatinib ± endocrine therapy. Dasatinib caused a dose-dependent decrease in proliferation in MCF7-TAMR cells and resensitized them to tamoxifen and fulvestrant but not in HCC1428-TAMR. In contrast, in estrogen-deprived conditions, dasatinib increased the proliferation rate of parental-MCF7 cells and had no effect on MCF7-LTED or HCC1428-LTED. Treatment with dasatinib caused a decrease in src-phosphorylation and inhibition of downstream pathways, including AKT and ERK1/2 in all cell lines tested, but only the MCF7-TAMR showed a concomitant decrease in markers of cell cycle progression. Inhibition of src also caused a significant decrease in cell migration in both MCF7-LTED and MCF7-TAMR cells. Finally, we showed that, in MCF7-TAMR cells, in contrast to tamoxifen sensitive cell lines, ER is expressed throughout the cell rather than being restricted to the nucleus and that treatment with dasatinib resulted in nuclear shuttling of ER, which was associated with an increase in ER-mediated transcription. These data suggest that src has differential effects in endocrine-resistant cell lines, particularly in tamoxifen resistant models, with low ER genomic activity, providing further evidence of the importance of patient selection for clinical trials testing dasatinib utility in ER+ breast cancer.

Dataset Information

UCH-L1-mediated Down-regulation of Estrogen Receptor ? Contributes to Insensitivity to Endocrine Therapy for Breast Cancer.

Publications

UCH-L1-mediated Down-regulation of Estrogen Receptor α Contributes to Insensitivity to Endocrine Therapy for Breast Cancer.

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