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DNAJC12 as a Mediator Between ESR1 and ERBB4 in Breast Carcinoma Cells.

ABSTRACT: Mutation of the DNAJC12 gene is typically associated with non-progressive Parkinsonism, but is also detectable in breast carcinoma where its contribution and mechanisms are unexplored. In breast carcinoma, ESR1 was positively correlated with DNAJC12 and ERBB4, and DNAJC12 was positively correlated with ERBB4. We used the GEO2R tool to compare differential gene expression of MCF-7 cells, following ESR1 knockdown (GEO database, E-GEOD-27473 array), and found decreased expression of DNAJC12 and ERBB4 in ESR1-silenced MCF-7 cells. The number of identical genes having correlativity with ESR1, DNAJC12, or ERBB4 was 12,165 (66.41%). These results suggest that ESR1 can promote the expression of DNAJC12 and ERBB4, and DNAJC12 can enhance the expression of ERBB4 in MCF-7 cells, implying that there may be a regulatory network among these three genes.

SUBMITTER: Lin M

PROVIDER: S-EPMC7943744 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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DNAJC12 as a Mediator Between ESR1 and ERBB4 in Breast Carcinoma Cells.

Lin Mianjie M Wang Ya-Nan YN Ye Yixin Y Xiong Zhelei Z Guo Fengbiao F Chen Haibin H

Frontiers in oncology 20210224

Mutation of the DNAJC12 gene is typically associated with non-progressive Parkinsonism, but is also detectable in breast carcinoma where its contribution and mechanisms are unexplored. In breast carcinoma, ESR1 was positively correlated with DNAJC12 and ERBB4, and DNAJC12 was positively correlated with ERBB4. We used the GEO2R tool to compare differential gene expression of MCF-7 cells, following ESR1 knockdown (GEO database, E-GEOD-27473 array), and found decreased expression of DNAJC12 and ERB ...[more]

PMID: 33718139

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Project description:Chemical manipulation of estrogen receptor alpha ligand binding domain structural mobility tunes receptor lifetime and influences breast cancer therapeutic activities. Selective estrogen receptor modulators (SERMs) extend estrogen receptor alpha (ERα) cellular lifetime/accumulation. They are antagonists in the breast but agonists in the uterine epithelium and/or in bone. Selective estrogen receptor degraders/downregulators (SERDs) reduce ERα cellular lifetime/accumulation and are pure antagonists. Activating somatic ESR1 mutations Y537S and D538G enable resistance to first-line endocrine therapies. SERDs have shown significant activities in ESR1 mutant setting while few SERMs have been studied. To understand whether chemical manipulation of ERα cellular lifetime and accumulation influences antagonistic activity, we studied a series of methylpyrollidine lasofoxifene (Laso) derivatives that maintained the drug's antagonistic activities while uniquely tuning ERα cellular accumulation. These molecules were examined alongside a panel of antiestrogens in live cell assays of ERα cellular accumulation, lifetime, SUMOylation, and transcriptional antagonism. High-resolution x-ray crystal structures of WT and Y537S ERα ligand binding domain in complex with the methylated Laso derivatives or representative SERMs and SERDs show that molecules that favor a highly buried helix 12 antagonist conformation achieve the greatest transcriptional suppression activities in breast cancer cells harboring WT/Y537S ESR1. Together these results show that chemical reduction of ERα cellular lifetime is not necessarily the most crucial parameter for transcriptional antagonism in ESR1 mutated breast cancer cells. Importantly, our studies show how small chemical differences within a scaffold series can provide compounds with similar antagonistic activities, but with greatly different effects of the cellular lifetime of the ERα, which is crucial for achieving desired SERM or SERD profiles.

Dataset Information

DNAJC12 as a Mediator Between ESR1 and ERBB4 in Breast Carcinoma Cells.

Publications

DNAJC12 as a Mediator Between ESR1 and ERBB4 in Breast Carcinoma Cells.

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