Expression of Estrogen and Progesterone Receptor in Tumor Stroma Predicts Favorable Prognosis of Cervical Squamous Cell Carcinoma

Objectives The aim of this study was to investigate the expression of estrogen receptor &agr; (ER&agr;) and progesterone receptor B (PRB) in the stroma and carcinoma tissues of cervical cancer and their relationship to clinical characteristics and the status of human papillomavirus (HPV) infection. Methods Expressional levels of ER&agr; and PRB in tissue blocks of 95 cervical carcinomas were independently scored by 2 pathologists. Human papillomavirus DNA, viral load, and genotypes were determined by polymerase chain reaction. Clinical characteristics were reviewed from chart and cancer registry. Results Estrogen receptor &agr; and PRB were mainly expressed in the stroma but not in the carcinoma tissues of the cervical cancer, and their expressions were highly correlated. More stromal ER&agr;s were found in early-stage tumors than in advanced-stage tumors. Greater stromal expressions of ER&agr; and PRB were associated with a more favorable prognosis (P = 0.018 and P = 0.004, respectively). The expressions were not related to the differentiation of cancer, the status of HPV infection, the HPV load, or the genotype. In multivariate analysis, stromal ER&agr; and PRB expressions were independently associated with a lower risk of mortality. The adjusted hazard ratios of mortality for low and high expressions of ER&agr; were 0.19 (95% confidential interval [95% CI], 0.04–0.87) and 0.15 (95% CI, 0.03–0.81), respectively, whereas for low and high expressions of PRB hazard ratios were 0.46 (95% CI, 0.19–1.16) and 0.24 (95% CI, 0.06–0.96), respectively. Conclusions This study showed that stromal ER&agr; and PRB expressions are independent prognostic indicators of cervical squamous cell carcinoma.

[1]  C. Hsieh,et al.  Antiestrogen use reduces risk of cervical neoplasia in breast cancer patients: a population-based study , 2016, Oncotarget.

[2]  A. Bajpai,et al.  Role of estrogen receptor alpha in human cervical cancer-associated fibroblasts: a transcriptomic study , 2016, Tumor Biology.

[3]  M. Newton,et al.  Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling , 2015, Proceedings of the National Academy of Sciences.

[4]  F. DeMayo,et al.  Progesterone signaling inhibits cervical carcinogenesis in mice. , 2013, The American journal of pathology.

[5]  K. Korach,et al.  Requirement for Stromal Estrogen Receptor Alpha in Cervical Neoplasia , 2013, Hormones and Cancer.

[6]  E. Korobowicz,et al.  Estrogen and progesterone receptor expression in HPV-positive and HPV-negative cervical carcinomas. , 2011, Oncology reports.

[7]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[8]  Kathleen R. Cho,et al.  Tumorigenesis and Neoplastic Progression Loss of Estrogen Receptor 1 Enhances Cervical Cancer Invasion , 2022 .

[9]  Z. Werb,et al.  Tumors as organs: complex tissues that interface with the entire organism. , 2010, Developmental cell.

[10]  Jeffrey W. Pollard,et al.  Macrophage Diversity Enhances Tumor Progression and Metastasis , 2010, Cell.

[11]  R. Zeillinger,et al.  Oestrogen and progesterone receptor expression in patients with adenocarcinoma of the uterine cervix and correlation with various clinicopathological parameters. , 2010, Anticancer research.

[12]  P. Lambert,et al.  Prevention and treatment of cervical cancer in mice using estrogen receptor antagonists , 2009, Proceedings of the National Academy of Sciences.

[13]  N. Kiviat,et al.  Depot-medroxyprogesterone acetate and combined oral contraceptive use and cervical neoplasia among women with oncogenic human papillomavirus infection. , 2009, American journal of obstetrics and gynecology.

[14]  K. Korach,et al.  Requirement for estrogen receptor alpha in a mouse model for human papillomavirus-associated cervical cancer. , 2008, Cancer research.

[15]  V. Beral,et al.  Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16 573 women with cervical cancer and 35 509 women without cervical cancer from 24 epidemiological studies , 2007, The Lancet.

[16]  M. Eijkemans,et al.  Prognosis of adenocarcinoma of the uterine cervix: p53 expression correlates with higher incidence of mortality , 2007, International journal of cancer.

[17]  Chien-Jen Chen,et al.  Quality assurance of genotyping array for detection and typing of human papillomavirus. , 2007, Journal of virological methods.

[18]  Joakim Dillner,et al.  Cervical carcinoma and reproductive factors: Collaborative reanalysis of individual data on 16,563 women with cervical carcinoma and 33,542 women without cervical carcinoma from 25 epidemiological studies , 2006, International journal of cancer.

[19]  Raghu Kalluri,et al.  Fibroblasts in cancer , 2006, Nature Reviews Cancer.

[20]  C. Wheeler,et al.  Hormonal contraceptive use, pregnancy and parity, and the risk of cervical intraepithelial neoplasia 3 among oncogenic HPV DNA‐positive women with equivocal or mildly abnormal cytology , 2005, International journal of cancer.

[21]  P. Cooke,et al.  Role of stromal-epithelial interactions in hormonal responses. , 2004, Archives of histology and cytology.

[22]  D. Wallwiener,et al.  Detection and Typing of Human Papillomavirus by E6 Nested Multiplex PCR , 2004, Journal of Clinical Microbiology.

[23]  S. Shapiro,et al.  Risk of invasive cancer of the cervix in relation to the use of injectable progestogen contraceptives and combined estrogen/progestogen oral contraceptives (South Africa) , 2003, Cancer Causes & Control.

[24]  P. Cooke,et al.  Epithelial-stromal tissue interaction in paramesonephric (Müllerian) epithelial differentiation. , 2001, Developmental biology.

[25]  T. Nakano,et al.  Progesterone receptor is a favorable prognostic factor of radiation therapy for adenocarcinoma of the uterine cervix. , 2000, International journal of radiation oncology, biology, physics.

[26]  S. Masood,et al.  Expression and prognostic significance of estrogen and progesterone receptors in adenocarcinoma of the uterine cervix. An immunocytochemical study , 1993, Cancer.

[27]  I. Konishi,et al.  Immunohistochemical analysis of estrogen receptors, progesterone receptors, Ki‐67 antigen, and human papillomavirus DNA in normal and neoplastic epithelium of the uterine cervix , 1991, Cancer.

[28]  I. Konishi,et al.  Estrogen receptor localization in normal and neoplastic epithelium of the uterine cervix , 1990, Cancer.

[29]  P Chambon,et al.  Two distinct estrogen‐regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. , 1990, The EMBO journal.

[30]  W. Remmele,et al.  [Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue]. , 1987, Der Pathologe.

[31]  L. Twiggs,et al.  Prognostic importance of progesterone and estrogen receptors in cancer of the uterine cervix , 1986, Cancer.

[32]  L. Twiggs,et al.  Cytoplasmic estrogen and progesterone receptors in primary cervical carcinoma: clinical and histopathologic correlates. , 1983, American journal of obstetrics and gynecology.

[33]  G. Cunha.  Stromal induction and specification of morphogenesis and cytodifferentiation of the epithelia of the Mullerian ducts and urogenital sinus during development of the uterus and vagina in mice. , 1976, The Journal of experimental zoology.

[34]  M. Muyan,et al.  Single-chain estrogen receptors (ERs) reveal that the ERalpha/beta heterodimer emulates functions of the ERalpha dimer in genomic estrogen signaling pathways. , 2004, Molecular and cellular biology.

[35]  A. Scharl,et al.  Immunohistochemical study of distribution of estrogen receptors in corpus and cervix uteri , 2004, Archives of Gynecology and Obstetrics.

[36]  E S Hafez,et al.  Uterine cervix. , 1969, Science.