Cover Image

Papillary Thyroid Cancer-Promoting Activities of Combined Oral Contraceptive Components

Mehdi Hedayati, Sadegh Rajabi, Abdolrahim Nikzamir

Background: Thyroid cancer is more common in women at reproductive age, suggesting the relationship between its high-incidence and therapeutic use of hormonal medications, such as oral contraceptives (OCPs). The aim of this study was to identify the effect of low-dose combined OCP (LD-COC) on proliferation, apoptosis, and migration of human papillary thyroid cancer (PTC) BCPAP cell line. Materials and Methods: BCPAP cells were cultured and treated with the combination of 90nM levonorgestrel (LNG) and 20nM ethinylestradiol (EE) for 48 hours. Afterward, using 3-(4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT) assay, the proliferation of the cells was measured. Apoptosis was determined by using a Caspase-3 ELISA kit. Migratory properties of combined LNG and EE were studied through wound scratch assay. The expression levels of pro-apoptotic factor BAX, anti-apoptotic factor Bcl2, and proliferation marker Ki67 were analyzed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blotting. Results: Upon treatment with the combination of LNG and EE, proliferation and migration of BCPAP cells were significantly enhanced. However, LNG and EE remarkably inhibited apoptosis of these cells. Furthermore, treating PTC cells with combined LNG and EE caused a marked increase in the expression of Bcl2 and Ki67 and a considerable decrease in BAX levels (P˂ 0.05). Conclusion: Our data linked the use of COCs and the progression and aggressiveness of PTC, suggesting the role of these hormonal compounds as promoting factors for PTC tumors. Despite these observations, further investigations will be required to fully establish the pathogenic impact of these medications on PTC. [GMJ.2020;9:e1648] 

Papillary Thyroid Cancer; Oral Contraceptives; Proliferation; Apoptosis

Khaled H, Al Lahloubi N, Rashad N. A review on thyroid cancer during pregnancy: Multitasking is required. J Adv Res. 2016;7(4):565-70.

https://doi.org/10.1016/j.jare.2016.02.007

PMid:27408758 PMCid:PMC4921779

Rahbari R, Zhang L, Kebebew E. Thyroid cancer gender disparity. Future Oncol. 2010;6(11):1771-9.

https://doi.org/10.2217/fon.10.127

PMid:21142662 PMCid:PMC3077966

Wang P, Lv L, Qi F, Qiu F. Increased risk of papillary thyroid cancer related to hormonal factors in women. Tumour Biol. 2015;36(7):5127-32.

https://doi.org/10.1007/s13277-015-3165-0

PMid:25669169

Kilfoy BA, Devesa SS, Ward MH, Zhang Y, Rosenberg PS, Holford TR et al. Gender is an age-specific effect modifier for papillary cancers of the thyroid gland. Cancer Epidemiol Biomarkers Prev. 2009;18(4):1092-100.

https://doi.org/10.1158/1055-9965.EPI-08-0976

PMid:19293311 PMCid:PMC2667567

Horn-Ross PL, Canchola AJ, Ma H, Reynolds P, Bernstein L. Hormonal factors and the risk of papillary thyroid cancer in the California Teachers Study cohort. Cancer Epidemiol Biomarkers Prev. 2011.

https://doi.org/10.1158/1055-9965.EPI-11-0381

PMid:21791618 PMCid:PMC3288117

Rossing MA, Voigt LF, Wicklund KG, Williams M, Daling JR. Use of exogenous hormones and risk of papillary thyroid cancer (Washington, United States). Cancer Causes Control. 1998;9(3):341-9.

https://doi.org/10.1023/A:1008833422577

PMid:9684714

Sakoda LC, Horn-Ross PL. Reproductive and menstrual history and papillary thyroid cancer risk: the San Francisco Bay Area thyroid cancer study. Cancer Epidemiol Biomarkers Prev. 2002;11(1):51-7.

Rossing MA, Voigt LF, Wicklund KG, Daling JR. Reproductive factors and risk of papillary thyroid cancer in women. Am J Epidemiol. 2000;151(8):765-72.

https://doi.org/10.1093/oxfordjournals.aje.a010276

PMid:10965973

Kabat GC, Kim MY, Wactawski-Wende J, Lane D, Wassertheil-Smoller S, Rohan TE. Menstrual and reproductive factors, exogenous hormone use, and risk of thyroid carcinoma in postmenopausal women. Cancer Causes Control. 2012;23(12):2031-40.

https://doi.org/10.1007/s10552-012-0084-x

PMid:23090034

Bitzer J. Oral contraceptives in adolescent women. Best Pract Res Clin Endocrinol Metab. 2013;27(1):77-89.

https://doi.org/10.1016/j.beem.2012.09.005

PMid:23384748

Brynhildsen J. Combined hormonal contraceptives: prescribing patterns, compliance, and benefits versus risks. Ther Adv Drug Saf. 2014;5(5):201-13.

https://doi.org/10.1177/2042098614548857

PMid:25360241 PMCid:PMC4212440

Pakgohar M, Malekian S. Impact of Oral Contraceptive Pills (LDs) and Condoms on Women's Sexual Function: A Prospective Study in Iran. Nurs Heal. 2015;3(2):47-50.

Veljkovic M, Veljkovic S. [The risk of breast cervical, endometrial and ovarian cancer in oral contraceptive users]. Med Pregl. 2010;63(9-10):657-61.

https://doi.org/10.2298/MPNS1010657V

PMid:21446095

Colditz GA. Decline in breast cancer incidence due to removal of promoter: combination estrogen plus progestin. Breast Cancer Res. 2007;9(4):108.

https://doi.org/10.1186/bcr1736

PMid:17666116 PMCid:PMC2206710

Kubba A. Breast cancer and the pill. Journal of the Royal Society of Medicine. 2003;96(6):280-3.

https://doi.org/10.1177/014107680309600606

PMid:12782692 PMCid:PMC539508

Eldien MMS, Abdou AG, Rageh T, Abdelrazek E, Elkholy E. Immunohistochemical expression of ER-alpha and PR in papillary thyroid carcinoma. Ecancermedicalscience. 2017;11:748.

https://doi.org/10.3332/ecancer.2017.748

PMid:28717394 PMCid:PMC5493440

Jalali-Nadoushan MR, Amirtouri R, Davati A, Askari S, Siadati S. Expression of estrogen and progesterone receptors in papillary thyroid carcinoma. Caspian J Intern Med. 2016;7(3):183-7.

Sturniolo G, Zafon C, Moleti M, Castellvi J, Vermiglio F, Mesa J. Immunohistochemical Expression of Estrogen Receptor-alpha and Progesterone Receptor in Patients with Papillary Thyroid Cancer. Eur Thyroid J. 2016;5(4):224-30.

https://doi.org/10.1159/000452488

PMid:28101486 PMCid:PMC5216192

Chen D, Qi W, Zhang P, Guan H, Wang L. Expression of the estrogen receptor alpha, progesterone receptor and epidermal growth factor receptor in papillary thyroid carcinoma tissues. Oncol Lett. 2015;10(1):317-20.

https://doi.org/10.3892/ol.2015.3223

PMid:26171022 PMCid:PMC4487165

Di Vito M, De Santis E, Perrone GA, Mari E, Giordano MC, De Antoni E et al. Overexpression of estrogen receptor-alpha in human papillary thyroid carcinomas studied by laser- capture microdissection and molecular biology. Cancer Sci. 2011;102(10):1921-7.

https://doi.org/10.1111/j.1349-7006.2011.02017.x

PMid:21707866

Zeng Q, Chen GG, Vlantis AC, van Hasselt CA. Oestrogen mediates the growth of human thyroid carcinoma cells via an oestrogen receptor-ERK pathway. Cell Prolif. 2007;40(6):921-35.

https://doi.org/10.1111/j.1365-2184.2007.00471.x

PMid:18021179 PMCid:PMC6495898

Rajoria S, Suriano R, Shanmugam A, Wilson YL, Schantz SP, Geliebter J et al. Metastatic phenotype is regulated by estrogen in thyroid cells. Thyroid. 2010;20(1):33-41.

https://doi.org/10.1089/thy.2009.0296

PMid:20067378 PMCid:PMC2833180

Khan S, Shukla S, Sinha S, Lakra AD, Bora HK, Meeran SM. Centchroman suppresses breast cancer metastasis by reversing epithelial-mesenchymal transition via downregulation of HER2/ERK1/2/MMP-9 signaling. Int J Biochem Cell Biol. 2015;58:1-16.

https://doi.org/10.1016/j.biocel.2014.10.028

PMid:25448414

Clark AG, Vignjevic DM. Modes of cancer cell invasion and the role of the microenvironment. Curr Opin Cell Biol. 2015;36:13-22.

https://doi.org/10.1016/j.ceb.2015.06.004

PMid:26183445

Sales Gil R, Vagnarelli P. Ki-67: More Hidden behind a 'Classic Proliferation Marker'. Trends Biochem Sci. 2018;43(10):747-8.

https://doi.org/10.1016/j.tibs.2018.08.004

PMid:30131191

Singh L, Pushker N, Saini N, Sen S, Sharma A, Bakhshi S et al. Expression of pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins in human retinoblastoma. Clin Exp Ophthalmol. 2015;43(3):259-67.

https://doi.org/10.1111/ceo.12397

PMid:25132102

Ceresini G, Morganti S, Graiani V, Saccani M, Milli B, Usberti E et al. Estrogen receptor (ER)-beta, but not ER-alpha, is present in thyroid vessels: immunohistochemical evaluations in multinodular goiter and papillary thyroid carcinoma. Thyroid. 2006;16(12):1215-20.

https://doi.org/10.1089/thy.2006.16.1215

PMid:17199431

Bufalo N.E., Campos A.H., Rocha A.G., Cunha L.L., Pimentel G.D., Batista F.A. et al. ERα IMMUNOSTAINING: AN AUXILIARY DIAGNOSTIC TOOL OF FOLLICULAR THYROID LESIONS. 15TH INTERNATIONAL THYROID CONGRESS PROGRAM AND MEETING ABSTRACTS; Florida, USA. Thyroid: Mary Ann Liebert, Inc.; 2015.

Kawabata W, Suzuki T, Moriya T, Fujimori K, Naganuma H, Inoue S et al. Estrogen receptors (alpha and beta) and 17beta-hydroxysteroid dehydrogenase type 1 and 2 in thyroid disorders: possible in situ estrogen synthesis and actions. Mod Pathol. 2003;16(5):437-44.

https://doi.org/10.1097/01.MP.0000066800.44492.1B

PMid:12748250

Mori M, Naito M, Watanabe H, Takeichi N, Dohi K, Ito A. Effects of sex difference, gonadectomy, and estrogen on N-methyl-N-nitrosourea induced rat thyroid tumors. Cancer Res. 1990;50(23):7662-7.

Dong W, Zhang H, Li J, Guan H, He L, Wang Z et al. Estrogen Induces Metastatic Potential of Papillary Thyroid Cancer Cells through Estrogen Receptor alpha and beta. Int J Endocrinol. 2013;2013:941568.

https://doi.org/10.1155/2013/941568

PMid:24222765 PMCid:PMC3810507

Rajoria S, Parmar P, Schantz S, Schaefer S, Chaudhuri D, Tiwari R et al. Significance of estrogen receptor in thyroid cancer: Molecular link of epidemiologic observations. Cancer Res. 2008;68(9 Supplement):4254.

Vivacqua A, Bonofiglio D, Albanito L, Madeo A, Rago V, Carpino A et al. 17beta-estradiol, genistein, and 4-hydroxytamoxifen induce the proliferation of thyroid cancer cells through the g protein-coupled receptor GPR30. Mol Pharmacol. 2006;70(4):1414-23.

https://doi.org/10.1124/mol.106.026344

PMid:16835357

Kumar A, Klinge CM, Goldstein RE. Estradiol-induced proliferation of papillary and follicular thyroid cancer cells is mediated by estrogen receptors alpha and beta. Int J Oncol. 2010;36(5):1067-80.

https://doi.org/10.3892/ijo_00000588

PMid:20372779

Zeng Q, Chen G, Vlantis A, Tse G, van Hasselt C. The contributions of oestrogen receptor isoforms to the development of papillary and anaplastic thyroid carcinomas. J Pathol. 2008;214(4):425-33.

https://doi.org/10.1002/path.2297

PMid:18085520

Lee ML, Chen GG, Vlantis AC, Tse GM, Leung BC, van Hasselt CA. Induction of thyroid papillary carcinoma cell proliferation by estrogen is associated with an altered expression of Bcl-xL. Cancer J. 2005;11(2):113-21.

https://doi.org/10.1097/00130404-200503000-00006

PMid:15969986

Warth A, Cortis J, Soltermann A, Meister M, Budczies J, Stenzinger A et al. Tumour cell proliferation (Ki-67) in non-small cell lung cancer: a critical reappraisal of its prognostic role. Br J Cancer. 2014;111(6):1222-9.

https://doi.org/10.1038/bjc.2014.402

PMid:25051406 PMCid:PMC4453847

Li LT, Jiang G, Chen Q, Zheng JN. Ki67 is a promising molecular target in the diagnosis of cancer (review). Mol Med Rep. 2015;11(3):1566-72.

https://doi.org/10.3892/mmr.2014.2914

PMid:25384676

Lee O, Choi MR, Christov K, Ivancic D, Khan SA. Progesterone receptor antagonism inhibits progestogen-related carcinogenesis and suppresses tumor cell proliferation. Cancer Lett. 2016;376(2):310-7.

https://doi.org/10.1016/j.canlet.2016.04.010

PMid:27080304

Moore MR, Spence JB, Kiningham KK, Dillon JL. Progestin inhibition of cell death in human breast cancer cell lines. J Steroid Biochem Mol Biol. 2006;98(4-5):218-27.

https://doi.org/10.1016/j.jsbmb.2005.09.008

PMid:16466914

Jeng MH, Parker CJ, Jordan VC. Estrogenic potential of progestins in oral contraceptives to stimulate human breast cancer cell proliferation. Cancer Res. 1992;52(23):6539-46.

Dressing GE, Alyea R, Pang Y, Thomas P. Membrane progesterone receptors (mPRs) mediate progestin induced antimorbidity in breast cancer cells and are expressed in human breast tumors. Horm Cancer. 2012;3(3):101-12.

https://doi.org/10.1007/s12672-012-0106-x

PMid:22350867

Refbacks

  • There are currently no refbacks.