title: Inverse Relationship between Progesterone Receptor and Myc in Endometrial Cancer.
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.
authors: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States of America.
authors: Tamar
authors: T
authors: Kavlashvili
authors: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States of America.
authors: Yichen
authors: Y
authors: Jia
authors: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States of America.
authors: Donghai
authors: D
authors: Dai
authors: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States of America.|Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, United States of America.
authors: Xiangbing
authors: X
authors: Meng
authors: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States of America.
authors: Kristina W
authors: KW
authors: Thiel
authors: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States of America.|Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, United States of America.
authors: Kimberly K
authors: KK
authors: Leslie
authors: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States of America.|Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, United States of America.
authors: Shujie
authors: S
authors: Yang
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000503:physiopathology; D047628:Estrogen Receptor alpha / Q000032:analysis / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D055786:Gene Knockout Techniques; D016259:Genes, myc / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D000077767:Panobinostat; D060888:Real-Time Polymerase Chain Reaction; D011980:Receptors, Progesterone / Q000032:analysis* / Q000502:physiology; D015854:Up-Regulation
chemical_list: D047628:Estrogen Receptor alpha; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D011980:Receptors, Progesterone; D000077767:Panobinostat