Inverse Relationship between Progesterone Receptor and Myc in Endometrial Cancer

Tamar Kavlashvili; Yichen Jia; Donghai Dai; Xiangbing Meng; Kristina W Thiel; Kimberly K Leslie; Shujie Yang

doi:10.1371/journal.pone.0148912

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Inverse Relationship between Progesterone Receptor and Myc in Endometrial Cancer

Journal article

Open access

Peer reviewed

Inverse Relationship between Progesterone Receptor and Myc in Endometrial Cancer

Tamar Kavlashvili, Yichen Jia, Donghai Dai, Xiangbing Meng, Kristina W Thiel, Kimberly K Leslie and Shujie Yang

PloS one, Vol.11(2), pp.e0148912-e0148912

2016

DOI: 10.1371/journal.pone.0148912

PMCID: PMC4747472

PMID: 26859414

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Abstract

Endometrial cancer, the most common gynecologic malignancy, is a hormonally-regulated disease. Response to progestin therapy positively correlates with hormone receptor expression, in particular progesterone receptor (PR). However, many advanced tumors lose PR expression. We recently reported that the efficacy of progestin therapy can be significantly enhanced by combining progestin with epigenetic modulators, which we term "molecularly enhanced progestin therapy." What remained unclear was the mechanism of action and if estrogen receptor α (ERα), the principle inducer of PR, is necessary to restore functional expression of PR via molecularly enhanced progestin therapy. Therefore, we modeled advanced endometrial tumors that have lost both ERα and PR expression by generating ERα-null endometrial cancer cell lines. CRISPR-Cas9 technology was used to delete ERα at the genomic level. Our data demonstrate that treatment with a histone deacetylase inhibitor (HDACi) was sufficient to restore functional PR expression, even in cells devoid of ERα. Our studies also revealed that HDACi treatment results in marked downregulation of the oncogene Myc. We established that PR is a negative transcriptional regulator of Myc in endometrial cancer in the presence or absence of ERα, which is in contrast to studies in breast cancer cells. First, estrogen stimulation augmented PR expression and decreased Myc in endometrial cancer cell lines. Second, progesterone increased PR activity yet blunted Myc mRNA and protein expression. Finally, overexpression of PR by adenoviral transduction in ERα-null endometrial cancer cells significantly decreased expression of Myc and Myc-regulated genes. Analysis of the Cancer Genome Atlas (TCGA) database of endometrial tumors identified an inverse correlation between PR and Myc mRNA levels, with a corresponding inverse correlation between PR and Myc downstream transcriptional targets SRD5A1, CDK2 and CCNB1. Together, these data reveal a previously unanticipated inverse relationship between the tumor suppressor PR and the oncogene Myc in endometrial cancer.

Genes, myc - physiology

Panobinostat

Up-Regulation

Endometrial Neoplasms - chemistry

Humans

Endometrial Neoplasms - physiopathology

Gene Knockout Techniques

Blotting, Western

Receptors, Progesterone - analysis

Endometrial Neoplasms - genetics

Receptors, Progesterone - physiology

Cell Line, Tumor

Estrogen Receptor alpha - analysis

Female

Histone Deacetylase Inhibitors - pharmacology

Indoles - pharmacology

Estrogen Receptor alpha - physiology

Gene Expression Regulation, Neoplastic - drug effects

Gene Expression Regulation, Neoplastic - physiology

Hydroxamic Acids - pharmacology

Real-Time Polymerase Chain Reaction

Details

Title: Subtitle: Inverse Relationship between Progesterone Receptor and Myc in Endometrial Cancer
Creators: Tamar Kavlashvili - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States of America
Yichen Jia - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States of America
Donghai Dai - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States of America
Xiangbing Meng - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, United States of America
Kristina W Thiel - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States of America
Kimberly K Leslie - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, United States of America
Shujie Yang - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, United States of America
Resource Type: Journal article
Publication Details: PloS one, Vol.11(2), pp.e0148912-e0148912
DOI: 10.1371/journal.pone.0148912
PMID: 26859414
PMCID: PMC4747472
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: United States
Grant note: R01 CA184101 / NCI NIH HHS R01 CA099908 / NCI NIH HHS K12 HD063117 / NICHD NIH HHS R01CA184101 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01CA99908 / NCI NIH HHS
Language: English
Date published: 2016
Academic Unit: Pathology; Obstetrics and Gynecology
Record Identifier: 9983931733602771

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