Decreased expression of estrogen receptors alpha and beta in peripheral blood lymphocytes from the endometrial cancer patients and women with endometriosis

Aim: Endometriosis and endometrial cancer are described as typical estrogen-dependent gynaecological diseases. The question arises if estrogens, working through their receptors, could influence the immunological activity of lymphocytes in these disorders. Here, we evaluated transcriptional expression of the estrogen receptors alpha and beta (ERα and ERβ) in T lymphocytes isolated from the peripheral blood in endometrial cancer and endometriosis patients. Methods: Peripheral blood was collected from ten patients with endometrial cancer, nine with endometriosis, and ten disease-free controls. After isolation of the T lymphocytes, purity was confirmed by flow cytometry and the relative level of ERα and ERβ mRNA was determined using RT-qPCR analysis. Results: Both ERα and ERβ were significantly decreased in T lymphocytes isolated from patients with either endometrial cancer or endometriosis when compared to the healthy controls. We measured no difference in the mRNA levels of ERα between endometrial cancer patients and endometriosis group, but ERβ expression in endometrial cancer women was twice as high than in the endometriosis group. Conclusion: Decreased transcription of nuclear estrogen receptor isoforms characterizes T lymphocytes from women with endometrial cancer and endometriosis.

Endometriosis; Pelvic Pain; Endometrium Cancer; Steroid Hormones; Hormone Receptors; Molecular Medicine; Growth

Factors

[1] Lambert K.C., Curran E.M., Judy B.M., Milligan G.N., Lubahn D.B., Estes D.M.: “Estrogen receptor alpha (ERalpha) deficiency in macrophages results in increased stimulation of CD4+ T cells while 17beta-estradiol acts through ERalpha to increase IL-4 and GATA-3 expression in CD4+ T cells independent of antigen presentation”. J. Immunol., 2005, 175, 5716.

[2] Phiel K.L., Henderson R.A., Adelman S.J., Elloso M.M.: “Differ- ential estrogen receptor gene expression in human peripheral blood mononuclear cell populations”. Immunol. Lett., 2005, 97, 107.

[3] Pierdominici M., Maselli A., Colasanti T., Ortona E.: “Estrogen re- ceptors profiles in human peripheral blond lymphocytes”. Immunol. Lett., 2010, 132, 79.

[4] Shim G.J., Gherman D., Kim H.J., Omoto Y., Iwase H., Bouton D., et al.: “Differential expression of oestrogen receptors in human sec- ondary lymphoid tissues”. J. Pathol., 2005, 208, 408.

[5] Tai P., Wang J., Jin H., Song X., Song X., Yan J., et al.: “Induction of regulatory T cells by physiological levels of estrogen”. J. Cell. Physiol. 2008, 214, 456.

[6] Rider V., Li X., Peterson G., Dawson J., Kimler B.F., Abdou N.I.: “Differential expression of estrogen receptors in women with sys- temic lupus erythematosus”. J. Rheumatol., 2006, 33, 1093.

[7] Maselli A., Conti F., Alessandri C., Colasanti T., Barbati C., Vomero M., et al.: “Low expression of estrogen receptor beta in T lympho- cytes and high serum levels of anti-estrogen receptor alpha antibod- ies impact disease activity in female patients with systemic lupus erythematosus”. Biol. Sex. Differ., 2016, 7, 3.

[8] Lax S.F., Pizer E.S., Ronnett B.M., Kurman R.J.: “Comparison of estrogen and progesterone receptor, Ki-67, and p53 immunoreactiv- ity in uterine endometrioid carcinoma and endometrioid carcinoma with squamous, mucinous, secretory, and ciliated cell differentia- tion”. Human. Pathol., 1998, 29, 924.

[9] Ghering P.A., Linda Van Le, Olatidoye B., Geradts J.: “Estrogen receptor status, determined by immunohistochemistry, as a predictor of the recurrence of stage I endometrial carcinoma”. Cancer, 1999, 8986, 2083.

[10] Sliwinski T., Sitarek P., Stetkiewicz T., Sobczuk A., Blasiak J.: “Polymorphism of the ERα and CYP1B1 genes in a Polish subpop- ulation”. J. Obstet. Gynaecol. Res., 2010, 36, 311.

[11] Attar E., Bulun S.: “Aromatase inhibitors: the next generation of therapeutics for endometriosis”? Fertil. Steril., 2006, 85, 1307.

[12] Halis G., Mechsner S., Ebert A.: “The diagnosis and treatment of deep infiltrating endometriosis”. Dtsch. Arztebl. Int. 2010, 107, 446.

[13] Stygar D., Westlund P., Eriksson H., Sahlin L.: “Identification of wild type and variants of oestrogen receptors in polymorphonuclear and mononuclear leucocytes”. Clin. Endocrinol., 2006, 64, 74.

[14] Ning C., Xie B., Zhang L., Shan W., Yang B., Luo X., et al.: “Infil- trating macrophages induce ERalpha expression through an IL-17A- mediated epigenetic mechanizm to sensitize endometria cancer cells to estrogen”. Cancer Res., 2016, 76, 1354.

[15] Berstein L.M., Tchernobrovkina A.E., Gamajunova V.B., Ko- valevskij A.J., Vasilyev D.A., Chepik O.F., et al.: “Tumor estro- gen content and clinico-morphological and endocrine features of en- dometrial cancer”. J. Cancer Res. Clin. Oncol., 2003, 129, 245.

[16] Bulun S.E.: “ Endometriosis”. N. Engl. J. Med. 2009, 360, 268.

[17] Wallace A.E., Gibson D.A., Saunders P.T.K., Jabbour H.N.: “In- flammatory events in endometrial adenocarcinoma”. J. Endocrinol., 2010, 206, 141.

[18] Couse J.F., Korach K.S.: “Estrogen receptor null mice: what have we learned and where will they lead us”? Endocr. Rev., 1999, 20, 358.

[19] Hall J.M., McDonell D.P.: “The estrogen receptor β-isoform (ER β) of the human estrogen receptor modulates ERα transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens”. Endocrinol. 1999, 140, 5566.

[20] Jazaeri A.A., Nunes K.J., Dalton M.S., Xu M., Shupnik M.A., Rice L.W.: “Well-differentiated adenocarcinomas and poorly- differentiated mixed mullerian tumors have altered ER and PR iso- forms expressions”. Oncog., 2001, 20, 6965.

[21] Hale G.E., Hughes C.L., Cline J.M.: “Endometrial cancer: hormonal factors, the perimenopausal “window of risk”, and isoflavones”. J. Clin. Endocrinol. Metab., 2002, 87, 3.

[22] Xue Q., Lin Z., Cheng Y.H., Huang C.C., Marsh E., Yin P., et al.: “Promoter methylation regulates estrogen estrogen receptor 2 in hu- man endometrium and endometriosis”. Biol. Reprod., 2007, 77, 681.

[23] Jones R.K., Bulmer J.N., Searle R.F.: “Phenotypic and functional studies of leukocytes in human endometrium and endometriosis”. Hum. Reprod. Update, 1998, 4, 702.

[24] Harris H.A.: “Estrogen receptor-beta: recent lessons from in vivo studies”. Mol. Endocrinol., 2007, 21, 1.