ABSTRACT
Although the uterine cervix responds to the female sex hormone change, the role of progesterone in cervical cancer is poorly understood. It has been shown that medroxyprogesterone acetate (MPA) regresses cervical cancer in the transgenic mouse model expressing human papillomavirus type 16 E6 and E7 oncogenes. As MPA interacts most strongly with progesterone receptor (PR), we reasoned that PR would contribute to MPA-induced regression of cervical cancer. We also hypothesized that estrogen influences the therapeutic activity of MPA because it promotes cervical cancer growth in the same mouse model. The present study showed that the deletion of Pgr in the cervical cancer cells ablated the MPA's therapeutic effect in the human papillomavirus transgenic mouse model. Additionally, estrogen attenuated cancer regression by MPA in the same model system. These observations indicate that MPA can effectively regress cervical cancer only when cancer cells express PR and estrogen levels are low. These results suggest that, if translatable, MPA should be administered when estrogen levels are low in patients with PR-positive cervical cancer.
Subject(s)
Epithelial Cells , Estrogens/metabolism , Neoplasm Proteins , Neoplasms, Experimental , Progestins/pharmacology , Receptors, Progesterone , Uterine Cervical Neoplasms , Animals , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Gene Deletion , Male , Mice , Mice, Transgenic , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/genetics , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Receptors, Progesterone/genetics , Receptors, Progesterone/metabolism , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/pathologyABSTRACT
There has been little progress for several decades in modalities to treat cervical cancer. While the cervix is a hormone-sensitive tissue, physiologic roles of estrogen receptor α (ERα), progesterone receptor (PR), and their ligands in this tissue are poorly understood. It has hampered critical assessments of data in early epidemiologic and clinical studies for cervical cancer. Experimental evidence obtained from studies using mouse models has provided new insights into the molecular mechanism of ERα and PR in cervical cancer. In a mouse model expressing human papillomavirus (HPV) oncogenes, exogenous estrogen promotes cervical cancer through stromal ERα. In the same mouse model, genetic ablation of PR promotes cervical carcinogenesis without exogenous estrogen. Medroxyprogesterone acetate, a PR-activating drug, regresses cervical cancer in the mouse model. These results support that ERα and PR play opposite roles in cervical cancer. They further support that ERα inhibition and PR activation may be translated into valuable treatment for a subset of cervical cancers.
Subject(s)
Uterine Cervical Neoplasms , Animals , Cervix Uteri , Disease Models, Animal , Estrogens/therapeutic use , Female , Gonadal Steroid Hormones/therapeutic use , Humans , Mice , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/geneticsABSTRACT
Tumor-suppressor genes (TSG) are often deleted or transcriptionally suppressed in cancer. PGR codes for progesterone receptor (PR), a transcription factor whose function depends on its ligand. Although PR expression is often undetectable in cervical cancer, its relevance to the endocrine-related etiology of this prevalent gynecological disease remains unclear. In this study, we show that the deletion of one Pgr allele in cervical epithelium promoted spontaneous cervical cancer in human papilloma viral oncogene-expressing transgenic mice as efficiently as the ablation of both Pgr alleles. We also show that tumors arising in the transgenic mice with one or both Pgr alleles did not express PR or expressed at the reduced levels compared with the normal epithelium. PR status correlated with estrogen receptor α (ERα) status in the mouse model and the Cancer Genome Atlas (TCGA) dataset. TCGA data analyses revealed that PGR expression significantly decreased in cervical cancer and that the biallelic deletion of PGR was rare. Furthermore, low PGR expression was associated with poor prognosis in young patients with cervical cancer. These discoveries point to PGR as a haploinsufficient TSG in the uterine cervix. They also raise the possibility that the restoration of PGR expression may improve the survival rate. IMPLICATIONS: The decreased expression of PR may increase the risk of cervical cancer in human papillomavirus-infected women. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/1/42/F1.large.jpg.
Subject(s)
Genes, Tumor Suppressor/physiology , Receptors, Progesterone/metabolism , Uterine Cervical Neoplasms/genetics , Animals , Female , Humans , Mice , Mice, TransgenicABSTRACT
Cervical dysplastic lesions called cervical intraepithelial neoplasias (CINs) need be treated to prevent cervical cancer. Currently available surgical procedures are effective, but the development of noninvasive treatment is warranted. In human papillomavirus transgenic mice engineered to express human papillomavirus type 16 E6 and E7, short-term treatment with 17ß-estradiol induces CINs that progress to cervical cancer if the treatment is continued. In the present study, this mouse model was used to determine whether medroxyprogesterone acetate (MPA), a progestin drug, is chemopreventive. Human papillomavirus transgenic mice bearing CIN lesions were treated with MPA plus 17ß-estradiol. Unlike control mice treated with 17ß-estradiol alone, cervical cancer was absent in the MPA-treated mice. This observation suggests that MPA prevented CIN from progressing to invasive cancer. MPA was associated with inhibited cell proliferation and the promotion of apoptosis in CIN lesions. Confirming the role of the progesterone receptor, the preventive effect of MPA was absent in human papillomavirus transgenic mice in which the expression of progesterone receptor was genetically ablated. These results suggest that MPA is efficient in treating progesterone receptor-positive CIN lesions. These findings provide the basis for a biomarker-driven clinical trial of the secondary prevention of cervical cancer.
Subject(s)
Medroxyprogesterone Acetate/pharmacology , Papillomaviridae/isolation & purification , Papillomavirus Infections/complications , Receptors, Progesterone/metabolism , Uterine Cervical Dysplasia/prevention & control , Uterine Cervical Neoplasms/prevention & control , Animals , Antineoplastic Agents, Hormonal/pharmacology , Female , Humans , Mice , Mice, Inbred CBA , Mice, Transgenic , Papillomavirus Infections/virology , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/virology , Uterine Cervical Dysplasia/metabolism , Uterine Cervical Dysplasia/pathology , Uterine Cervical Dysplasia/virologyABSTRACT
Studies using K14E6/K14E7 transgenic mice expressing E6 and E7 oncoprotein of human papillomavirus type 16 (HPV16) have demonstrated that estrogen (E2) is required for the genesis and growth of cervical cancer. Our prior study using the same mouse model has showed that progestin drug medroxyprogesterone acetate (MPA) promotes regression of primary cervical cancer. In the present study, we use the same transgenic mouse model to determine whether the cancer recurs after MPA therapy. Cervical cancer recurred even if MPA treatment was continued. Unlike primary cervical cancer, the cancer recurred even in the absence of exogenous E2 when MPA treatment was ceased. Furthermore, recurrent cervical cancer did not fully regress upon MPA treatment. Our results support that MPA fails to completely eliminate primary cervical cancer cells and that remaining cancer cells grow independent of exogenous E2 and are refractory to MPA.