Metabotropic glutamate receptor 1 disrupts mammary acinar architecture and initiates malignant transformation of mammary epithelial cells

Teh, Jessica L.F.; Shah, Raj; Cava, Stephanie La; Dolfi, Sonia; Mehta, Madhura S.; Kongara, Sameera; Price, Sandy M.; Ganesan, Shridar; Reuhl, Kenneth R.; Hirshfield, Kim M.; Karantza, Vassiliki; Chen, Suzie

doi:10.1007/s10549-015-3365-8

Cited by 28 publications

(32 citation statements)

References 40 publications

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“…5 Lymphoma and prostate adenocarcinoma aside, other neoplasms may merit exclusion because mGluR1 receptors are known to be expressed in melanoma and breast adenocarcinoma. 11,12 One patient likely had zoster-induced parainfectious neurologic autoimmunity, a phenomenon reported in patients with NMDA receptor encephalitis with preceding herpes simplex encephalitis. 13 The neurologic significance of mGluR1-IgG seropositivity detected in serum, primarily by CBA, in 2 German patients with MS findings was unclear.…”

Section: Resultsmentioning

confidence: 99%

Metabotropic glutamate receptor type 1 autoimmunity

et al. 2016

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Objective: To describe retrospectively the clinical associations of immunoglobulin G (IgG) targeting metabotropic glutamate receptor 1 (mGluR1-IgG).Methods: Specimens of 9 patients evaluated on a service basis in the Mayo Clinic Neuroimmunology Laboratory by tissue-based immunofluorescence assay (IFA) yielded a robust, synaptic immunostaining pattern consistent with mGluR1-IgG (serum, 9; CSF, 2 available). Transfected HEK293 cell-based assay (CBA) confirmed mGluR1 specificity in all 11 specimens. A further 2 patients were detected in Germany primarily by CBA.Results: The median symptom onset age for the 11 patients was 58 years (range 33-81 years); 6 were male. All 9 Mayo Clinic patients had subacute onset of cerebellar ataxia, 4 had dysgeusia, 1 had psychiatric symptoms, and 1 had cognitive impairment. All were evaluated for malignancy, but only 1 was affected (cutaneous T-cell lymphoma). One developed ataxia post-herpes zoster infection. Head MRIs were generally atrophic or normal-appearing, and CSF was inflammatory in just 1 of 5 tested, though mGluR1-IgG was detected in both specimens submitted. Five patients improved (attributable to immunotherapy in 4, spontaneously in 1), 3 stabilized (attributable to immunotherapy in 2, cancer therapy in 1), and 1 progressively declined (untreated). The 2 German patients had ataxia, but fulfilled multiple sclerosis diagnostic criteria (1 relapsing-remitting, 1 progressive). However, both had histories of hematologic malignancy (acute lymphocytic leukemia and mantle cell lymphoma), and had mGluR1-IgG detected in serum by CBA (weakly positive on tissue-based IFA).Conclusions: mGluR1 autoimmunity represents a treatable form of cerebellar ataxia. Dysgeusia may be a diagnostic clue. Paraneoplastic, parainfectious, or idiopathic causes may occur. Metabotropic glutamate receptor 1 (mGluR1) is a G-protein-coupled receptor, activation of which facilitates long-term depression of parallel fiber-Purkinje cell synapses critical for cerebellar motor learning. 1 mGluR1-immunoglobulin G (IgG) autoantibody is a biomarker of autoimmune cerebellar ataxia, reported in a paraneoplastic context (usually lymphoma) or without neoplasm detected.2-5 Given the limited literature, we report 11 patients (with archived specimens and recorded histories) in whom mGluR1 autoimmunity was encountered, in order to determine the disease spectrum.METHODS Standard protocol approvals, registrations, and patient consents. This study was carried out with the approval of institutional review boards and written informed consents were obtained.Patients and assays. Nine patients were identified in the Mayo Clinic Neuroimmunology Laboratory by 2 mechanisms. All specimens were clinically submitted for paraneoplastic antibody evaluation. (1) Four patients were identified by reviewing archived descriptions of mouse tissue-based immunofluorescence assays (IFAs) for 1,074 patients with unclassified neural antibody staining (1996. Thirty-two patients had descriptions resembling the reported mGluR1-IgG staining pat...

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Section: Resultsmentioning

confidence: 99%

Metabotropic glutamate receptor type 1 autoimmunity

et al. 2016

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“…CLDN6 shRNA target sequence is GGCAAG GTGTACGACTCA and HIF-1α shRNA target sequence is GTTACGTTCCTTCGATCAG. Lentiviruses or plasmids are transfected into cells according to instructions, and stable clones were generated as previously described [25].…”

Section: Plasmid and Transfectionmentioning

confidence: 99%

A SUMOylation-dependent HIF-1α/CLDN6 negative feedback mitigates hypoxia-induced breast cancer metastasis

Jia

Guo

Qiu

et al. 2020

J Exp Clin Cancer Res

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Background: We have previously described CLDN6 as a tumor suppressor gene in breast cancer. Here, a new finding is that CLDN6 was upregulated under hypoxia, a commonly recognized factor that promotes tumor metastasis. In this study, we aim to explain this confusing finding and delineate the role of CLDN6 in the breast cancer metastasis induced by hypoxia. Methods: RNAi and ChIP assays were used to confirm that CLDN6 is transcriptional regulated by HIF-1α. mRNA seq and KEGG analysis were performed to define the downstream pathways of CLDN6. The roles of the CLDN6/SENP1/ HIF-1α signaling on tumor metastasis were evaluated by function experiments and clinical samples. Finally, the possible transcription factor of SENP1 was suspected and then validated by ChIP assay. Results: We demonstrated a previously unrecognized negative feedback loop exists between CLDN6 and HIF-1α. CLDN6 was transcriptionally up-regulated by HIF-1α under hypoxia. On the other hand, in cytoplasm CLDN6 combines and retains β-catenin, a transcription factor of SENP1, causing β-catenin degradation and preventing its nuclear translocation. This process reduced SENP1 expression and prevented the deSUMOylation of HIF-1α, ultimately leading to HIF-1α degradation and breast cancer metastasis suppression. Conclusions: Our data provide a molecular mechanistic insight indicating that CLDN6 loss may lead to elevated HIF-1α-driven breast cancer metastasis in a SUMOylation-dependent manner.

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“…Riluzole has shown anti-tumor activity in preclinical models of multiple cancers, including melanoma, glioblastoma, and breast cancer [25][26][27][28][29][30][31]. In several (but not all) of these reports, Riluzole-mediated growth inhibition is attributed to increased expression of metabotropic glutamate receptors (mGluRs, GRMs).…”

Section: Resultsmentioning

confidence: 99%

Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

Stires

Olukoya

et al. 2020

Preprint

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BackgroundResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a significant clinical problem. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis. A benzothiazole-based glutamate release inhibitor with several context-dependent mechanism(s) of action, Riluzole has shown anti-tumor activity in multiple malignancies, including melanoma, glioblastoma, and breast cancer. In several (but not all) of these studies, Riluzole-mediated growth inhibition is attributed to increased expression of metabotropic glutamate receptors (mGluRs, GRMs). We recently reported that acquisition of Tamoxifen resistance in a cellular model of invasive lobular breast cancer is accompanied by the upregulation of GRM mRNA expression and growth inhibition by Riluzole.MethodsIn the current study, we tested the ability of Riluzole to reduce cell growth, alone and in combination with endocrine therapy, in a diverse set of ER+ invasive ductal and lobular breast cancer-derived cell lines, primary breast tumor explant cultures, and the estrogen-independent, ESR1-mutated invasive lobular breast cancer patient-derived xenograft model HCI-013EI.ResultsSingle-agent Riluzole suppressed the growth of ER+ invasive ductal and lobular breast cancer cell lines in vitro, inducing a histologic subtype-associated cell cycle arrest (G0-G1 for ductal, G2-M for lobular). In an invasive lobular, endocrine resistant model, Riluzole induced apoptosis and reduced phosphorylation of multiple pro-survival signaling molecules, including Akt/mTOR, CREB, and Src/Fak family kinases. Riluzole in combination with either Fulvestrant or 4-hydroxytamoxifen additively or synergistically suppressed ER+ breast cancer cell growth in vitro. The combination of Riluzole plus Fulvestrant significantly reduced proliferation in primary breast tumor explant cultures, and inhibited HCI-013EI xenograft growth in vivo significantly earlier than Fulvestrant alone.ConclusionsThese findings suggest Riluzole combined with endocrine therapy may offer therapeutic benefit in diverse ER+ breast cancers, including lobular breast cancer.

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Metabotropic glutamate receptor 1 disrupts mammary acinar architecture and initiates malignant transformation of mammary epithelial cells

Cited by 28 publications

References 40 publications

Metabotropic glutamate receptor type 1 autoimmunity

Metabotropic glutamate receptor type 1 autoimmunity

A SUMOylation-dependent HIF-1α/CLDN6 negative feedback mitigates hypoxia-induced breast cancer metastasis

Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

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