Melatonin modulates aromatase activity and expression in endothelial cells

Alvarez-García,Virginia; González,Alicia; Martínez-Campa,Carlos; Alonso-González,Carolina; Cos,Samuel

doi:10.3892/or.2013.2314

Melatonin modulates aromatase activity and expression in endothelial cells

Authors:
- Virginia Alvarez-García
- Alicia González
- Carlos Martínez-Campa
- Carolina Alonso-González
- Samuel Cos
View Affiliations

Affiliations: Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, 39011 Santander, Spain
Published online on: February 28, 2013 https://doi.org/10.3892/or.2013.2314
Pages: 2058-2064

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Melatonin is known to suppress the development of endocrine-responsive breast cancers by interacting with the estrogen signaling pathways. Paracrine interactions between malignant epithelial cells and proximal stromal cells are responsible for local estrogen biosynthesis. In human breast cancer cells and peritumoral adipose tissue, melatonin downregulates aromatase, which transforms androgens into estrogens. The presence of aromatase on endothelial cells indicates that endothelial cells may contribute to tumor growth by producing estrogens. Since human umbilical vein endothelial cells (HUVECs) express both aromatase and melatonin receptors, the aim of the present study was to evaluate the ability of melatonin to regulate the activity and expression of aromatase on endothelial cells, thus, modulating local estrogen biosynthesis. In the present study, we demonstrated that melatonin inhibits the growth of HUVECs and reduces the local biosynthesis of estrogens through the downregulation of aromatase. These results are supported by three lines of evidence. Firstly, 1 mM of melatonin counteracted the testosterone-induced cell proliferation of HUVECs, which is dependent on the local biosynthesis of estrogens from testosterone by the aromatase activity of the cells. Secondly, we found that 1 mM of melatonin reduced the aromatase activity of HUVECs. Finally, by real‑time RT-PCR, we demonstrated that melatonin significantly downregulated the expression of aromatase as well as its endothelial-specific aromatase promoter region I.7. We conclude that melatonin inhibits aromatase activity and expression in HUVECs by regulating gene expression of specific aromatase promoter regions, thereby reducing the local production of estrogens.

View Figures

View References

1	Russo IH and Russo J: Role of hormones in mammary cancer initiation and progression. J Mammary Gland Biol Neoplasia. 3:49–61. 1998. View Article : Google Scholar : PubMed/NCBI
2	Russo J and Russo IH: The role of estrogen in the initiation of breast cancer. J Steroid Biochem Mol Biol. 102:89–96. 2006. View Article : Google Scholar : PubMed/NCBI
3	Orlando L, Schiavone P, Fedele P, et al: Molecularly targeted endocrine therapies for breast cancer. Cancer Treat Rev. 36(Suppl 3): S67–S71. 2010. View Article : Google Scholar : PubMed/NCBI
4	Landeghem AA, Poortman J, Nabuurs M and Thijssen JH: Endogenous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue. Cancer Res. 45:2900–2906. 1985.PubMed/NCBI
5	Bulun SE, Lin Z, Imir G, et al: Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev. 57:359–383. 2005. View Article : Google Scholar : PubMed/NCBI
6	Bulun SE, Price TM, Aitken J, Mahendroo MS and Simpson ER: A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrin Metab. 77:1622–1628. 1993. View Article : Google Scholar
7	Yue W, Wang JP, Hamilton CJ, Demers LM and Santen RJ: In situ aromatization enhances breast tumor estradiol levels and cellular proliferation. Cancer Res. 58:927–932. 1998.PubMed/NCBI
8	Santen RJ and Harvey HA: Use of aromatase inhibitors in breast carcinoma. Endocr Relat Cancer. 6:75–92. 1999. View Article : Google Scholar : PubMed/NCBI
9	Brodie AM and Njar VC: Aromatase inhibitors and their application in breast cancer treatment. Steroids. 65:171–179. 2000. View Article : Google Scholar : PubMed/NCBI
10	Hill SM and Blask DE: Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF-7) in culture. Cancer Res. 48:6121–6126. 1988.PubMed/NCBI
11	Cos S and Sánchez-Barceló EJ: Melatonin and mammary pathological growth. Front Neuroendocrinol. 21:133–170. 2000. View Article : Google Scholar : PubMed/NCBI
12	Blask DE, Sauer LA and Dauchy RT: Melatonin as a chronobiotic/anticancer agent: cellular, biochemical and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Topics Med Chem. 2:113–132. 2002. View Article : Google Scholar
13	Mediavilla MD, Sánchez-Barceló EJ, Tan DX, Manchester L and Reiter RJ: Basic mechanisms involved in the anti-cancer effects of melatonin. Curr Med Chem. 17:4462–4481. 2010. View Article : Google Scholar : PubMed/NCBI
14	Sánchez-Barceló EJ, Cos S, Fernández R and Mediavilla MD: Melatonin and mammary cancer: a short review. Endocr Relat Cancer. 10:153–159. 2003.
15	Cos S, González A, Martínez-Campa C, Mediavilla MD, Alonso-González C and Sánchez-Barceló EJ: Estrogen-signaling pathway: a link between breast cancer and melatonin oncostatic actions. Cancer Detect Prev. 30:118–128. 2006. View Article : Google Scholar : PubMed/NCBI
16	Cos S, González A, Martínez-Campa C, Mediavilla MD, Alonso-González C and Sánchez-Barceló EJ: Melatonin as a selective estrogen enzyme modulator. Curr Cancer Drug Targets. 8:691–702. 2008. View Article : Google Scholar : PubMed/NCBI
17	González A, Cos S, Martínez-Campa C, Alonso-González C, Sánchez-Mateos S, Mediavilla MD and Sánchez-Barceló EJ: Selective estrogen enzyme modulator actions of melatonin in human breast cancer cells. J Pineal Res. 45:86–92. 2008.PubMed/NCBI
18	Zhou D, Wang J, Chen E, Murai J, Siiteri PK and Chen S: Aromatase gene is amplified in MCF-7 human breast cancer cells. J Steroid Biochem Mol Biol. 46:147–153. 1993. View Article : Google Scholar : PubMed/NCBI
19	Ram PT, Kiefer T, Silverman M, Song Y, Brown GM and Hill SM: Estrogen receptor transactivation in MCF-7 breast cancer cells by melatonin and growth factors. Mol Cell Endocrinol. 141:53–64. 1998. View Article : Google Scholar : PubMed/NCBI
20	Ram PT, Dai J, Yuan L, Dong C, Kiefer TL, Lai L and Hill SM: Involvement of the mt1 melatonin receptor in human breast cancer. Cancer Lett. 179:141–150. 2002. View Article : Google Scholar : PubMed/NCBI
21	Cos S, Martínez-Campa C, Mediavilla MD and Sánchez-Barceló EJ: Melatonin modulates aromatase activity in MCF-7 human breast cancer cells. J Pineal Res. 38:136–142. 2005. View Article : Google Scholar : PubMed/NCBI
22	Cos S, González A, Güezmes A, Mediavilla MD, Martínez-Campa C, Alonso-González C and Sánchez-Barceló EJ: Melatonin inhibits the growth of DMBA-induced mammary tumors by decreasing the local biosynthesis of estrogens through the modulation of aromatase activity. Int J Cancer. 118:274–278. 2006. View Article : Google Scholar : PubMed/NCBI
23	Meng L, Zhou J, Sasano H, Suzuki T, Zeitoun KM and Bulun SE: Tumor necrosis factor α and interleukin 11 secreted by malignant breast epithelial cells inhibit adipocyte differentiation by selectively down-regulating CCAAT/enhancer binding protein α and peroxisome proliferator-activated receptor γ mechanism of desmoplastic reaction. Cancer Res. 61:2250–2255. 2001.
24	Bulun SE, Chen D, Lu M, et al: Aromatase excess in cancers of breast, endometrium and ovary. J Steroid Biochem Mol Biol. 106:81–96. 2007. View Article : Google Scholar : PubMed/NCBI
25	Alvarez-García V, González A, Alonso-González C, Martínez-Campa C and Cos S: Melatonin interferes in the desmoplastic reaction in breast cancer by regulating cytokine production. J Pineal Res. 52:282–290. 2012.PubMed/NCBI
26	González A, Alvarez-García V, Martínez-Campa C, Alonso-González C and Cos S: Melatonin promotes differentiation of 3T3-L1 fibroblasts. J Pineal Res. 52:12–20. 2012.PubMed/NCBI
27	Harada N, Sasano H, Murakami H, Ohkuma T, Nagura H and Takagi Y: Localized expression of aromatase in human vascular tissues. Circ Res. 84:1285–1291. 1999. View Article : Google Scholar : PubMed/NCBI
28	Mukherjee TK, Dinh H, Chaudhuri G and Nathan L: Testosterone attenuates expression of vascular cell adhesion molecule-1 by conversion to estradiol by aromatase in endothelial cells: implications in atherosclerosis. Proc Natl Acad Sci USA. 6:4055–4060. 2002. View Article : Google Scholar
29	Sebastian S and Bulun SE: A highly complex organization of the regulatory region of the human CYP19 (aromatase) gene revealed by the human genome project. J Clin Endocrinol Metab. 10:4600–4602. 2001. View Article : Google Scholar : PubMed/NCBI
30	Bulun SE, Lin Z, Zhao H, Lu M, Amin S, Reierstad S and Chen D: Regulation of aromatase expression in breast cancer tissue. Ann NY Acad Sci. 1155:121–131. 2009. View Article : Google Scholar : PubMed/NCBI
31	Chen D, Reierstad S, Lu M, Lin Z, Ishikawa H and Bulun SE: Regulation of breast cancer-associated aromatase promoters. Cancer Lett. 273:15–27. 2009. View Article : Google Scholar : PubMed/NCBI
32	Sebastian S, Takayama K, Shozu M and Bulun SE: Cloning and characterization of a novel endothelial promoter of the human CYP19 (aromatase P450) gene that is up-regulated in breast cancer tissue. Mol Endocrinol. 10:2243–2254. 2002. View Article : Google Scholar : PubMed/NCBI
33	Martínez-Campa C, González A, Mediavilla MD, Alonso-González C, Álvarez-García V, Sánchez-Barceló EJ and Cos S: Melatonin inhibits aromatase promoter expression by regulating cyclooxygenases expression and activity in breast cancer cells. Br J Cancer. 101:1613–1619. 2009.PubMed/NCBI
34	González A, Martínez-Campa C, Mediavilla MD, et al: Effects of MT₁ melatonin receptor overexpression on the aromatase-supressive effect of melatonin in MCF-7 human breast cancer cells. Oncol Rep. 4:947–953. 2007.
35	Cui P, Luo Z, Zhang H, et al: Effect and mechanism of melatonin's action on the proliferation of human umbilical vein endothelial cells. J Pineal Res. 4:358–362. 2006.
36	Cui P, Yu M, Luo Z, Dai M, Han J, Xiu R and Yang Z: Intracellular signaling pathways involved in cell growth inhibition of human vein endothelial cells by melatonin. J Pineal Res. 44:107–114. 2008.PubMed/NCBI
37	Ackerman GE, Smith ME, Mendelson CR, MacDonald PC and Simpson ER: Aromatization of androstenedione by human adipose tissue stromal cells in monolayer culture. J Clin Endocrinol Metab. 53:412–417. 1981. View Article : Google Scholar : PubMed/NCBI
38	Pasqualini JR: The selective estrogen enzyme modulators in breast cancer: a review. Biochim Biophys Acta. 1654:123–143. 2004.PubMed/NCBI
39	Pasqualini JR and Chetrite GS: Recent insight on the control of enzymes involved in estrogen formation and transformation in human breast cancer. J Steroid Biochem Mol Biol. 93:221–236. 2005. View Article : Google Scholar : PubMed/NCBI
40	Cos S and Sánchez-Barceló EJ: Melatonin, experimental basis for a possible application in breast cancer prevention and treatment. Histol Histopathol. 15:637–647. 2000.PubMed/NCBI
41	Molis TM, Spriggs LI and Hill SM: Modulation of estrogen receptor mRNA expression by melatonin in MCF-7 human breast cancer cells. Mol Endocrinol. 8:1681–1690. 1994.PubMed/NCBI
42	Hill SM, Spriggs LL, Simon MA, Muraoka H and Blask DE: The growth inhibitory action of melatonin on human breast cancer cells is linked to the estrogen response system. Cancer Lett. 64:249–256. 1992. View Article : Google Scholar : PubMed/NCBI
43	Garvin S, Nilsson UW and Dabrosin C: Effects of oestradiol and tamoxifen on VEGF, soluble VEGFR-1 and VEGFR-2 in breast cancer and endothelial cells. Br J Cancer. 9:1005–1010. 2005. View Article : Google Scholar : PubMed/NCBI
44	González A, Martínez-Campa C, Mediavilla MD, Alonso-González C, Sánchez-Barceló EJ and Cos S: Inhibitory effects of pharmacological doses of melatonin on aromatase activity and expression in rat glioma cells. Br J Cancer. 97:755–760. 2007.PubMed/NCBI
45	Knower KC, To SQ, Takagi K, Miki Y, Sasano H, Simpson ER and Clyne CD: Melatonin suppresses aromatase expression and activity in breast cancer associated fibroblasts. Breast Cancer Res Treat. 132:765–771. 2012. View Article : Google Scholar : PubMed/NCBI
46	Turner HE, Harris AL, Melmed S and Wass JA: Angiogenesis in endocrine tumors. Endocr Rev. 24:600–632. 2003. View Article : Google Scholar : PubMed/NCBI
47	García-Santos G, Antolín I, Herrera F, Martín V, Rodriguez-Blanco J, del Pilar Carrera M and Rodriguez C: Melatonin induces apoptosis in human neuroblastoma cancer cells. J Pineal Res. 41:130–135. 2006.
48	Sainz RM, Mayo JC, Tan DX, Leon J, Manchester L and Reiter RJ: Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independent mechanism. Prostate. 63:29–43. 2005. View Article : Google Scholar : PubMed/NCBI
49	Longatti P, Perin A, Rizzo V, Comai S, Giusti P and Costa CV: Ventricular cerebrospinal fluid melatonin concentrations investigated with an endoscopic technique. J Pineal Res. 42:113–118. 2007. View Article : Google Scholar : PubMed/NCBI
50	Maestroni GJ and Conti A: Melatonin in human breast cancer tissue: association with nuclear grade and estrogen receptor status. Lab Invest. 75:557–561. 1996.PubMed/NCBI