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.

• Authors: Hanan S Elsarraj, Kelli E Valdez, Yan Hong, Sandra L Grimm, Lawrence R Ricci, Fang Fan, Ossama Tawfik, Lisa May, Therese Cusick, Marc Inciardi, Mark Redick, Jason Gatewood, Onalisa Winblad, Susan Hilsenbeck, Dean P Edwards, Christy R Hagan, Andrew K Godwin, Carol Fabian, Fariba Behbod
• Journal: Cancer research (Cancer Res) Vol. 77 Issue 14 Pg. 3802-3813 (07 15 2017) ISSN: 1538-7445 [Electronic] United States
• PMID: 28515148 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Estrogens
• IKBKG protein, human
• Interleukin-6
• Intracellular Signaling Peptides and Proteins
• NEMO protein, mouse
• Promyelocytic Leukemia Protein
• Receptors, Estrogen
• Tumor Suppressor Proteins
• Progesterone
• I-kappa B Kinase

Topics

• Animals
• Breast Neoplasms (genetics, pathology)
• Cell Line, Tumor
• Estrogens (administration & dosage, metabolism)
• Female
• Humans
• I-kappa B Kinase (genetics, metabolism)
• Interleukin-6 (biosynthesis)
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• MCF-7 Cells
• Mammary Neoplasms, Experimental (chemically induced, genetics, metabolism)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Progesterone (administration & dosage, metabolism)
• Promyelocytic Leukemia Protein (genetics, metabolism)
• Receptors, Estrogen (genetics, metabolism)
• Signal Transduction
• Transcription, Genetic
• Tumor Suppressor Proteins (genetics, metabolism)