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ERRgamma mediates tamoxifen resistance in novel models of invasive lobular breast cancer.

ABSTRACT: One-third of all estrogen receptor (ER)-positive breast tumors treated with endocrine therapy fail to respond, and the remainder is likely to relapse in the future. Almost all data on endocrine resistance has been obtained in models of invasive ductal carcinoma (IDC). However, invasive lobular carcinomas (ILC) comprise up to 15% of newly diagnosed invasive breast cancers each year and, whereas the incidence of IDC has remained relatively constant during the last 20 years, the prevalence of ILC continues to increase among postmenopausal women. We report a new model of Tamoxifen (TAM)-resistant invasive lobular breast carcinoma cells that provides novel insights into the molecular mechanisms of endocrine resistance. SUM44 cells express ER and are sensitive to the growth inhibitory effects of antiestrogens. Selection for resistance to 4-hydroxytamoxifen led to the development of the SUM44/LCCTam cell line, which exhibits decreased expression of ERalpha and increased expression of the estrogen-related receptor gamma (ERRgamma). Knockdown of ERRgamma in SUM44/LCCTam cells by siRNA restores TAM sensitivity, and overexpression of ERRgamma blocks the growth-inhibitory effects of TAM in SUM44 and MDA-MB-134 VI lobular breast cancer cells. ERRgamma-driven transcription is also increased in SUM44/LCCTam, and inhibition of activator protein 1 (AP1) can restore or enhance TAM sensitivity. These data support a role for ERRgamma/AP1 signaling in the development of TAM resistance and suggest that expression of ERRgamma may be a marker of poor TAM response.

SUBMITTER: Riggins RB

PROVIDER: S-EPMC2701641 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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ERRgamma mediates tamoxifen resistance in novel models of invasive lobular breast cancer.

Riggins Rebecca B RB Lan Jennifer P-J JP Zhu Yuelin Y Klimach Uwe U Zwart Alan A Cavalli Luciane R LR Haddad Bassem R BR Chen Li L Gong Ting T Xuan Jianhua J Ethier Stephen P SP Clarke Robert R

Cancer research 20081101 21

One-third of all estrogen receptor (ER)-positive breast tumors treated with endocrine therapy fail to respond, and the remainder is likely to relapse in the future. Almost all data on endocrine resistance has been obtained in models of invasive ductal carcinoma (IDC). However, invasive lobular carcinomas (ILC) comprise up to 15% of newly diagnosed invasive breast cancers each year and, whereas the incidence of IDC has remained relatively constant during the last 20 years, the prevalence of ILC c ...[more]

PMID: 18974135

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Project description:One-third of all ER+ breast tumors treated with endocrine therapy fail to respond, and the remainder are likely to relapse in the future. Almost all data on endocrine resistance has been obtained in models of invasive ductal carcinoma (IDC). However, invasive lobular carcinomas (ILC) comprise up to 15% of newly diagnosed invasive breast cancers diagnosed each year and, while the incidence of IDC has remained relatively constant during the last 20 years, the prevalence of ILC continues to increase among postmenopausal women. We report a new model of Tamoxifen (TAM)-resistant invasive lobular breast carcinoma cells that provides novel insights into the molecular mechanisms of endocrine resistance. SUM44 cells express ER and are sensitive to the growth inhibitory effects of antiestrogens. Selection for resistance to 4-hydroxytamoxifen led to the development of the SUM44/LCCTam cell line, which exhibits decreased expression of estrogen receptor alpha (ERα) and increased expression of the estrogen-related receptor gamma (ERRγ). Knockdown of ERRγ in SUM44/LCCTam cells by siRNA restores TAM sensitivity, and overexpression of ERRγ blocks the growth-inhibitory effects of TAM in SUM44 and MDA-MB-134 VI lobular breast cancer cells. ERRγ-driven transcription is also increased in SUM44/LCCTam, and inhibition of activator protein 1 (AP1) can restore or enhance TAM sensitivity. These data support a role for ERRγ/AP1 signaling in the development of TAM resistance, and suggest that expression of ERRγ may be a marker of poor Tamoxifen response. Experiment Overall Design: Total RNA was extracted from sub-confluent T-25 cm^2 tissue culture flasks of SUM44 and LCCTam cells, then processed and arrayed. Microarray data quality was then assessed using several tools, including those recommended by Affymetrix and a series of additional QC measures. The Robust Multiple-Array Average (RMA) method was used to preprocess the raw gene expression data, as implemented in the Bioconductor project (http://bioconductor.org). We then isolated a reduced dimension dataset that included genes that exhibit ≥2 fold change, p<0.05 and genes with intensity ≥log2(10) in both SUM44 and SUM44/LCCTam groups. Data visualization before and after dimensionality reduction was facilitated by multidimensional scaling as estimated using Principal Component Analysis (PCA) and Discriminant Component Analysis (DCA), to ensure that the global structure of the data was not altered by dimensionality reduction procedures.

Project description:One-third of all ER+ breast tumors treated with endocrine therapy fail to respond, and the remainder are likely to relapse in the future. Almost all data on endocrine resistance has been obtained in models of invasive ductal carcinoma (IDC). However, invasive lobular carcinomas (ILC) comprise up to 15% of newly diagnosed invasive breast cancers diagnosed each year and, while the incidence of IDC has remained relatively constant during the last 20 years, the prevalence of ILC continues to increase among postmenopausal women. We report a new model of Tamoxifen (TAM)-resistant invasive lobular breast carcinoma cells that provides novel insights into the molecular mechanisms of endocrine resistance. SUM44 cells express ER and are sensitive to the growth inhibitory effects of antiestrogens. Selection for resistance to 4-hydroxytamoxifen led to the development of the SUM44/LCCTam cell line, which exhibits decreased expression of estrogen receptor alpha (ERÎ±) and increased expression of the estrogen-related receptor gamma (ERRÎ³). Knockdown of ERRÎ³ in SUM44/LCCTam cells by siRNA restores TAM sensitivity, and overexpression of ERRÎ³ blocks the growth-inhibitory effects of TAM in SUM44 and MDA-MB-134 VI lobular breast cancer cells. ERRÎ³-driven transcription is also increased in SUM44/LCCTam, and inhibition of activator protein 1 (AP1) can restore or enhance TAM sensitivity. These data support a role for ERRÎ³/AP1 signaling in the development of TAM resistance, and suggest that expression of ERRÎ³ may be a marker of poor Tamoxifen response. Experiment Overall Design: Total RNA was extracted from sub-confluent T-25 cm^2 tissue culture flasks of SUM44 and LCCTam cells, then processed and arrayed. Microarray data quality was then assessed using several tools, including those recommended by Affymetrix and a series of additional QC measures. The Robust Multiple-Array Average (RMA) method was used to preprocess the raw gene expression data, as implemented in the Bioconductor project (http://bioconductor.org). We then isolated a reduced dimension dataset that included genes that exhibit â¥2 fold change, p<0.05 and genes with intensity â¥log2(10) in both SUM44 and SUM44/LCCTam groups. Data visualization before and after dimensionality reduction was facilitated by multidimensional scaling as estimated using Principal Component Analysis (PCA) and Discriminant Component Analysis (DCA), to ensure that the global structure of the data was not altered by dimensionality reduction procedures.

Project description:BackgroundTamoxifen (TAM) resistance to invasive lobular cell carcinoma is a challenge for breast cancer treatment. This study explored the role of Aldo-keto reductase family 1 (AKR1) family in tamoxifen-resistant aggressive lobular breast cancer based on data mining.MethodsTAM-resistant invasive lobular breast cancer gene chip was downloaded from the Gene Expression Omnibus (GEO) database (accession-numbered as GSE96670). The online analytical tool GEO2R was used to screen for differentially expressed genes in TAM-resistant invasive lobular breast cancer cells and TAM-sensitive counterparts. A protein-protein interaction (PPI) networks were constructed using the STRING online platform and the Cytoscape software. GeneMANIA and GSCALite online tools were used to reveal the potential role of these hub genes in breast cancer progression and TAM resistance development. And the used the GSE67916 microarray data set to verify the differentially expression of these hub genes in breast cancer. The protein expression levels of AKR1C1, AKR1C2 and AKR1C3 in TAM-sensitive and resistant breast cancer cells were compared. The TAM sensitivity of breast cancer cells with or without AKR1C1, AKR1C2 or AKR1C3 gene manipulation was evaluated by cell viability assay.ResultsA total of 184 differentially expressed genes were screened. Compared with TAM sensitive breast cancer cells, 162 were up-regulated and 22 were down-regulated. The study identified several hub genes in the PPI network that may be involved in the development of TAM resistance of breast cancer, including signal transducer and activator of transcription 1 (STAT1), estrogen receptor alpha (ESR1), fibronectin1 (FN1), cytochrome P4501B1 (CYP1B1), AKR1C1, AKR1C2, AKR1C3 and uridine diphosphate glucuronosyltransferase (UGT) 1A family genes (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10). Compared with TAM-sensitive counterparts, the expression levels of AKR1C1, AKR1C2, and AKR1C3 were up-regulated in TAM-resistant breast cancer cells.ConclusionsOverexpression of each of these three genes significantly increased the resistance of breast cancer cells to TAM treatment, while their knockdown showed opposite effects, indicating that they are potential therapeutic target for the treatment of TAM-resistant breast cancer.

Project description:BACKGROUND:Invasive lobular breast carcinoma (ILC) is a histological subtype of breast cancer that is characterized by loss of E-cadherin and high expression of estrogen receptor alpha (ER?). In many cases, ILC is effectively treated with adjuvant aromatase inhibitors (AIs); however, acquired AI resistance remains a significant problem. METHODS:To identify underlying mechanisms of acquired anti-estrogen resistance in ILC, we recently developed six long-term estrogen-deprived (LTED) variant cell lines from the human ILC cell lines SUM44PE (SUM44; two lines) and MDA-MB-134VI (MM134; four lines). To better understand mechanisms of AI resistance in these models, we performed transcriptional profiling analysis by RNA-sequencing followed by candidate gene expression and functional studies. RESULTS:MM134 LTED cells expressed ER at a decreased level and lost growth response to estradiol, while SUM44 LTED cells retained partial ER activity. Our transcriptional profiling analysis identified shared activation of lipid metabolism across all six independent models. However, the underlying basis of this signature was distinct between models. Oxysterols were able to promote the proliferation of SUM44 LTED cells but not MM134 LTED cells. In contrast, MM134 LTED cells displayed a high expression of the sterol regulatory element-binding protein 1 (SREBP1), a regulator of fatty acid and cholesterol synthesis, and were hypersensitive to genetic or pharmacological inhibition of SREBPs. Several SREBP1 downstream targets involved in fatty acid synthesis, including FASN, were induced, and MM134 LTED cells were more sensitive to etomoxir, an inhibitor of the rate-limiting enzyme in beta-oxidation, than their respective parental control cells. Finally, in silico expression analysis in clinical specimens from a neo-adjuvant endocrine trial showed a significant association between the increase of SREBP1 expression and lack of clinical response, providing further support for a role of SREBP1 in the acquisition of endocrine resistance in breast cancer. CONCLUSIONS:Our characterization of a unique series of AI-resistant ILC models identifies the activation of key regulators of fatty acid and cholesterol metabolism, implicating lipid-metabolic processes driving estrogen-independent growth of ILC cells. Targeting these changes may prove a strategy for prevention and treatment of endocrine resistance for patients with ILC.

Project description:BackgroundBreast cancer (BC) is the most common malignancy in women and the second leading cause of cancer-related death; chemoresistance is still a clinical challenge mainly because of the different molecular features of this kind of tumour. Doxorubicin (Doxo) is widely used despite its adverse effects and the common onset of resistance. Chaperone-Mediated Autophagy (CMA) has been identified as an important mechanism through which chemotherapeutics can exert their cytotoxic effects and, in this context, LAMP-2A, the key player of CMA, can be a useful biomarker.MethodsA cohort of patients and breast cancer cells have been screened for Doxo effect and CMA activation by analysing the LAMP-2A level. Molecular silencing has been used to clarify CMA role in BC responsiveness to treatments. Low Doxo doses were combined with other drugs (TMZ or PX-478, a HIF-1α inhibitor) to evaluate their cytotoxic ability and their role in modulating CMA.ResultsIn this paper, we showed that CMA is an important mechanism mediating the responsiveness of breast cancer cell to different treatments (Doxo and TMZ, as suggested by triple negative cells that are TMZ-resistant and fails to activate CMA). The LAMP-2A expression level was specific for different cell lines and patient-derived tumour subtypes, and was also useful in discriminating patients for their survival rates. Moreover, molecular silencing or pharmacological blockage of HIF-1α activity reverted BC resistance to TMZ. The combination of low-dose Doxo with TMZ or PX-478 showed that the drug associations have synergistic behaviours.ConclusionHere, we demonstrated that CMA activity exerts a fundamental role in the responsiveness to different treatments, and LAMP-2A can be proposed as a reliable prognostic biomarker in breast cancer. In this context, HIF-1α, a potential target of CMA, can also be assessed as a valuable therapeutic target in BC in view of identifying new, more efficient and less toxic therapeutic drug combinations. Moreover, the possibility to combine Doxo with other drugs acting on different but coherent molecular targets could help overcome resistance and open the way to a decrease in the dose of the single drugs.

Dataset Information

ERRgamma mediates tamoxifen resistance in novel models of invasive lobular breast cancer.

Publications

ERRgamma mediates tamoxifen resistance in novel models of invasive lobular breast cancer.

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