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NEMO, a Transcriptional Target of Estrogen and Progesterone, Is Linked to Tumor Suppressor PML in Breast Cancer.

ABSTRACT: The beneficial versus detrimental roles of estrogen plus progesterone (E+P) in breast cancer remains controversial. Here we report a beneficial mechanism of E+P treatment in breast cancer cells driven by transcriptional upregulation of the NFκB modulator NEMO, which in turn promotes expression of the tumor suppressor protein promyelocytic leukemia (PML). E+P treatment of patient-derived epithelial cells derived from ductal carcinoma in situ (DCIS) increased secretion of the proinflammatory cytokine IL6. Mechanistic investigations indicated that IL6 upregulation occurred as a result of transcriptional upregulation of NEMO, the gene that harbored estrogen receptor (ER) binding sites within its promoter. Accordingly, E+P treatment of breast cancer cells increased ER binding to the NEMO promoter, thereby increasing NEMO expression, NFκB activation, and IL6 secretion. In two mouse xenograft models of DCIS, we found that RNAi-mediated silencing of NEMO increased tumor invasion and progression. This seemingly paradoxical result was linked to NEMO-mediated regulation of NFκB and IL6 secretion, increased phosphorylation of STAT3 on Ser727, and increased expression of PML, a STAT3 transcriptional target. In identifying NEMO as a pivotal transcriptional target of E+P signaling in breast cancer cells, our work offers a mechanistic explanation for the paradoxical antitumorigenic roles of E+P in breast cancer by showing how it upregulates the tumor suppressor protein PML. Cancer Res; 77(14); 3802-13. ©2017 AACR.

SUBMITTER: Elsarraj HS

PROVIDER: S-EPMC8236416 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Estrogen is involved in several physiological and pathological processes through estrogen receptor (ER)-mediated transcriptional gene regulation. miRNAs (miRs), which are noncoding RNA genes, may respond to estrogen and serve as posttranscriptional regulators in tumorigenic progression, especially in breast cancer; however, only limited information about this possibility is available. In the present study, we identified the estrogen-regulated miR-34b and investigated its functional role in breast cancer progression.Estrogen-regulated miRNAs were identified by using a TaqMan low density array. Our in vivo Tet-On system orthotopic model revealed the tumor-suppressive ability of miR-34b. Luciferase reporter assays and chromatin immunoprecipitation assay demonstrated miR-34b were regulated by p53-ER interaction.In this study, we identified one such estrogen downregulated miRNA, miR-34b, as an oncosuppressor that targets cyclin D1 and Jagged-1 (JAG1) in an ER+/wild-type p53 breast cancer cell line (MCF-7), as well as in ovarian and endometrial cells, but not in ER-negative or mutant p53 breast cancer cell lines (T47D, MBA-MB-361 and MDA-MB-435). There is a negative association between ER? and miR-34b expression levels in ER+ breast cancer patients. Tet-On induction of miR-34b can cause inhibition of tumor growth and cell proliferation. Also, the overexpression of miR-34b inhibited ER+ breast tumor growth in an orthotopic mammary fat pad xenograft mouse model. Further validation indicated that estrogen's inhibition of miR-34b expression was mediated by interactions between ER? and p53, not by DNA methylation regulation. The xenoestrogens diethylstilbestrol and zeranol also showed similar estrogenic effects by inhibiting miR-34b expression and by restoring the protein levels of the miR-34b targets cyclin D1 and JAG1 in MCF-7 cells.These findings reveal that miR-34b is an oncosuppressor miRNA requiring both ER+ and wild-type p53 phenotypes in breast cancer cells. These results improve our ability to develop new therapeutic strategies to target the complex estrogenic pathway in human breast cancer progression through miRNA regulation.

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NEMO, a Transcriptional Target of Estrogen and Progesterone, Is Linked to Tumor Suppressor PML in Breast Cancer.

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