Estrogen stimulates adenosine receptor expression subtypes in human breast cancer MCF-7 cell line

Azam Mohamadi, Mahmoud Aghaei, Mojtaba Panjehpour


Estrogen is a steroid hormone that plays a key role in the development and regulation of reproductive system. It has been shown that estrogen is related to breast cancer development through binding to its receptors. In order to uncover the estrogen effects on adenosine receptor expression, estrogen-positive    MCF-7 cells were used to treat with agonist and antagonist of estrogen and then the mRNA expression of adenosine receptor subtypes were evaluated. Estrogen-positive MCF-7 cells were treated with various concentrations of 17β estradiol (E2) as an estrogen agonist, and ICI 182,780 as an estrogen antagonist. The gene expression of adenosine receptor subtypes were detected by real time RT-PCR. The results of MTT assay showed that E2 increased cell viability in a dose dependent manner. The expression pattern of all adenosine receptor subtypes are as follow; A2b > A1 > A2a > A3 in untreated MCF-7 cells. Obtained results showed that E2 incubation at 0.001-0.01 µM led to up-regulation of A1ARs, A2aARs and A3ARs dose dependently. E2 at 0.001 µM also had no significant effect on A2bARs expression but, at higher doses induced a considerable decrease in mRNA A2bARs expression. Treatment with antagonist confirmed that up-regulation of these receptors is mediated by estrogen receptor. Taken together, our results indicate that treatment of MCF-7 cells with E2 led to up-regulation of adenosine receptors. However, these effects were partially restored by treatment with antagonist suggesting that such effects are mediated by estrogen receptors.


Breast cancer; MCF-7 cells; 17β Estradiol; Estrogen; Adenosine receptors

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Sullivan JM. Estrogen replacement therapy. Am J Med. 1996;101(4):56S-60S.

Rodriguez C, Patel AV, Calle EE, Jacob EJ, Thun MJ. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. Jama. 2001;285(11):1460-1465.

Lacey Jr JV, Mink PJ, Lubin JH, Sherman ME, Troisi R, Hartge P, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. Jama. 2002;288(3):334-341.

Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362(9382):419-427.

Chlebowski RT, Manson JE, Anderson GL, Cauley JA, Aragaki AK, Stefanick ML, et al. Estrogen plus progestin and breast cancer incidence and mortality in the Women’s Health Initiative Observational Study. J Natl Cancer Inst.. 2013;105(8):526-535.

Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. Jama. 2000;283(4):485-491.

Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med. 2006;354(3):270-282.

Germain D. Estrogen carcinogenesis in breast cancer. Endocrinol Metab Clin North Am.. 2011;40(3):473-484.

Cancer CGoHFiB. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet. 1997;350(9084):1047-1059.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin.. 2016;66(1):7-30.

Rebar RW. The breast and the physiology of lactation. Maternal-Fetal Medicine: Principles and Practice. 1994:144-161.

Vonderhaar BK. Regulation of development of the normal mammary gland by hormones and growth factors. Breast Cancer: Cellular and Molecular Biology: Springer; 1988. p. 251-266.

Henderson BE, Ross R, Bernstein L. Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation award lecture. Cancer Res. 1988;48(2):246-253.

Frasor J, Danes JM, Komm B, Chang KC, Lyttle CR, Katzenellenbogen BS. Profiling of estrogen up-and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology. 2003;144(10):4562-4574.

Burnstock G, Verkhratsky A. Long-term (trophic) purinergic signalling: purinoceptors control cell proliferation, differentiation and death. Cell Death Dis. 2010;1(1):e9.

Burnstock G. Purinergic signalling. British JPharmacol. 2006;147(S1):S172-S81.

Kumar V. Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go? Purinergic Signal. 2013;9(2):145-165.

Blay J, White TD, Hoskin DW. The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res. 1997;57(13):2602-2605.

Hoskin DW, Reynolds T, Blay J. Adenosine as a possible inhibitor of killer T‐cell activation in the microenvironment of solid tumours. International journal of cancer. 1994;59(6):854-855.

Merighi S, Mirandola P, Varani K, Gessi S, Leung E, Baraldi PG, et al. A glance at adenosine receptors: novel target for antitumor therapy. PharmacolTher. 2003;100(1):31-48.

Sachdeva S, Gupta M. Adenosine and its receptors as therapeutic targets: an overview. Saudi Pharm J. 2013;21(3):245-253.

Gessi S, Merighi S, Sacchetto V, Simioni C, Borea PA. Adenosine receptors and cancer. Biochim Biophys Acta. 2011;1808(5):1400-1412.

Fishman P, Bar-Yehuda S, Synowitz M, Powell J, Klotz K, Gessi S, et al. Adenosine receptors and cancer. Adenosine Receptors in Health and Disease: Springer; 2009. pp. 399-441.

Rosnera W, Hryb DJ, Khan MS, Nakhla AM, Romas NA. Androgen and estrogen signaling at the cell membrane via G-proteins and cyclic adenosine monophosphate. Steroids. 1999;64(1):100-106.

Canals M, Angulo E, Casadó V, Canela EI, Mallol J, Viñals F, et al. Molecular mechanisms involved in the adenosine A1 and A2A receptor‐induced neuronal differentiation in neuroblastoma cells and striatal primary cultures. J Neurochem. 2005;92(2):337-348.

Yasuda Y, Saito M, Yamamura T, Yaguchi T, Nishizaki T. Extracellular adenosine induces apoptosis in Caco-2 human colonic cancer cells by activating caspase-9/-3 via A2a adenosine receptors. J Gastroenterol. 2009;44(1):56-65.

Christofi FL, Zhang H, Yu JG, Guzman J, Xue J, Kim M, et al. Differential gene expression of adenosine A1, A2a, A2b, and A3 receptors in the human enteric nervous system. J Comp Neurol. 2001;439(1):46-64.

Panjehpour M, Karami-Tehrani F. Adenosine modulates cell growth in the human breast cancer cells via adenosine receptors. Oncol Res. 2007;16(12):575-585.

Gao Z, Li B-S, Day Y-J, Linden J. A3 adenosine receptor activation triggers phosphorylation of protein kinase B and protects rat basophilic leukemia 2H3 mast cells from apoptosis. Mol Pharmacol. 2001;59(1):76-82.

Chen J-F, Huang Z, Ma J, Zhu J, Moratalla R, Standaert D, et al. A2A adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J Neurosci. 1999;19(21):9192-9200.

Etique N, Grillier-Vuissoz I, Lecomte J, Flament S. Crosstalk between adenosine receptor (A2A isoform) and ERalpha mediates ethanol action in MCF-7 breast cancer cells. Oncol Rep. 2009;21(4):977-981.

Lin Z, Yin P, Reierstad S, O'Halloran M, Pearson E, Mutlu G, et al. Adenosine A1 receptor, a target and regulator of estrogen receptorα action, mediates the proliferative effects of estradiol in breast cancer. Oncogene. 2010;29(8):1114-1122.

Thomas E, Walton P, Thomas N, Dowsett M. Endocrinology: The effects of ICI 182, 780, a pure anti-oestrogen, on the hypothalamic-pituitary—gonadal axis and on endometrial proliferation in pre-menopausal women. Human Reproduction. 1994;9(11):1991-1996.

Feoktistov I, Biaggioni I. Adenosine A2B receptors. Pharmacol Rev. 1997;49(4):381-402.

Aherne CM, Kewley EM, Eltzschig HK. The resurgence of A2B adenosine receptor signaling. Biochim Biophys Acta. 2011;1808(5):1329-1339.

Fishman P, Bar-Yehuda S, Madi L, Cohn I. A3 adenosine receptor as a target for cancer therapy. Anti-cancer drugs. 2002;13(5):437-443.

Synowitz M, Glass R, Färber K, Markovic D, Kronenberg G, Herrmann K, et al. A1 adenosine receptors in microglia control glioblastoma-host interaction. Cancer Res. 2006;66(17):8550-8557.

Sun Y, Huang P. Adenosine A2B receptor: from cell biology to human diseases. Front Chem. 2016;4:37

Hajiahmadi S, Panjehpour M, Aghaei M, Shabani M. Activation of A2b adenosine receptor regulates ovarian cancer cell growth: involvement of Bax/Bcl-2 and caspase-3. Biochem Cell Biol. 2015;93(4):321-329.

Borea PA, Varani K, Vincenzi F, Baraldi PG, Tabrizi MA, Merighi S, et al. The A3 adenosine receptor: history and perspectives. Pharmacol Rev. 2015;67(1):74-102.


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