Tissue-Selective Regulation of Aromatase Expression by Calcitriol: Implications for Breast Cancer Therapy

Endocrinology - Tập 151 Số 1 - Trang 32-42 - 2010
Aruna V. Krishnan1, Srilatha Swami2, Lihong Peng2, Jining Wang2, Jacqueline Moreno2, David Feldman2
1Department of Medicine, Division of Endocrinology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305-5103, USA.
2Departments of Medicine, Division of Endocrinology, Stanford University School of Medicine, Stanford, California 94305

Tóm tắt

AbstractAromatase, the enzyme that catalyzes estrogen synthesis, is critical for the progression of estrogen receptor-positive breast cancer (BCa) in postmenopausal women. We show that calcitriol, the hormonally active form of vitamin D, regulates the expression of aromatase in a tissue-selective manner. Calcitriol significantly decreased aromatase expression in human BCa cells and adipocytes and caused substantial increases in human osteosarcoma cells (a bone cell model exhibiting osteoblast phenotype in culture) and modest increases in ovarian cancer cells. Calcitriol administration to immunocompromised mice bearing human BCa xenografts decreased aromatase mRNA levels in the tumors and the surrounding mammary adipose tissue but did not alter ovarian aromatase expression. In BCa cells, calcitriol also reduced the levels of prostaglandins (PGs), major stimulators of aromatase transcription, by suppressing the expression of cyclooxygenase-2 (which catalyzes PG synthesis) and increasing that of 15-hydroxyprostaglandin dehydrogenase (which catalyzes PG degradation). The mechanism of aromatase down-regulation by calcitriol in BCa cells is therefore 2-fold: a direct repression of aromatase transcription via promoter II through the vitamin D-response elements identified in this promoter and an indirect suppression by reducing the levels of PGs. Combinations of calcitriol with three different aromatase inhibitors (AIs) caused enhanced inhibition of BCa cell growth. The combination of calcitriol and an AI may have potential benefits for BCa therapy. In addition to augmenting the ability of AIs to inhibit BCa growth, calcitriol acting as a selective aromatase modulator that increases aromatase expression in bone would reduce the estrogen deprivation in bone caused by the AIs, thus ameliorating the AI-induced side effect of osteoporosis.

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Tài liệu tham khảo

Simpson, 2002, Aromatase—a brief overview., Annu Rev Physiol, 64, 93, 10.1146/annurev.physiol.64.081601.142703

Chen, 1998, Aromatase and breast cancer, Front Biosci, 3, d922, 10.2741/A333

Brodie A, Long B, Lu Q 1998 Aromatase expression in the human breast. Breast Cancer Res Treat 49(Suppl 1):S85–91; discussion S109–S119

Brueggemeier, 2006, Update on the use of aromatase inhibitors in breast cancer., Expert Opin Pharmacother, 7, 1919, 10.1517/14656566.7.14.1919

Geisler, 2005, Aromatase inhibition: translation into a successful therapeutic approach., Clin Cancer Res, 11, 2809, 10.1158/1078-0432.CCR-04-2187

Wheler, 2006, Adjuvant therapy with aromatase inhibitors for postmenopausal women with early breast cancer: evidence and ongoing controversy., Semin Oncol, 33, 672, 10.1053/j.seminoncol.2006.08.018

Confavreux, 2007, Estrogen-dependent increase in bone turnover and bone loss in postmenopausal women with breast cancer treated with anastrozole. Prevention with bisphosphonates., Bone, 41, 346, 10.1016/j.bone.2007.06.004

Mincey, 2006, Risk of cancer treatment-associated bone loss and fractures among women with breast cancer receiving aromatase inhibitors., Clin Breast Cancer, 7, 127, 10.3816/CBC.2006.n.021

Colston, 2005, 1663

Gombart, 2006, Vitamin D compounds: activity against microbes and cancer., Anticancer Res, 26, 2531

Krishnan, 2007, Calcitriol as a chemopreventive and therapeutic agent in prostate cancer: role of anti-inflammatory activity, J Bone Miner Res, 22, V74, 10.1359/jbmr.07s213

Trump, 2006, Vitamin D compounds: clinical development as cancer therapy and prevention agents., Anticancer Res, 26, 2551

Welsh, 2007, Targets of vitamin D receptor signaling in the mammary gland, J Bone Miner Res, 22, V86, 10.1359/jbmr.07s204

Enjuanes, 2003, Regulation of CYP19 gene expression in primary human osteoblasts: effects of vitamin D and other treatments., Eur J Endocrinol, 148, 519, 10.1530/eje.0.1480519

Yanase, 2003, Aromatase in bone: roles of Vitamin D3 and androgens., J Steroid Biochem Mol Biol, 86, 393, 10.1016/S0960-0760(03)00349-2

Simboli-Campbell, 1997, Comparative effects of 1,25(OH)2D3 and EB1089 on cell cycle kinetics and apoptosis in MCF-7 breast cancer cells., Breast Cancer Res Treat, 42, 31, 10.1023/A:1005772432465

Stoica, 1999, Regulation of estrogen receptor-α gene expression by 1, 25-dihydroxyvitamin D in MCF-7 cells., J Cell Biochem, 75, 640, 10.1002/(SICI)1097-4644(19991215)75:4<640::AID-JCB10>3.0.CO;2-8

Swami, 2000, 1α,25-Dihydroxyvitamin D3 down-regulates estrogen receptor abundance and suppresses estrogen actions in MCF-7 human breast cancer cells., Clin Cancer Res, 6, 3371

Krishnan, 2003, Inhibition of prostate cancer growth by vitamin D: Regulation of target gene expression., J Cell Biochem, 88, 363, 10.1002/jcb.10334

Moreno, 2005, Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells., Cancer Res, 65, 7917, 10.1158/0008-5472.CAN-05-1435

Livak, 2001, Analysis of relative gene expression data using real-time quantitative PCR and the 2[−ΔΔC(T)] method., Methods, 25, 402, 10.1006/meth.2001.1262

Chen, 2007, Generation of novel adipocyte monolayer cultures from embryonic stem cells., Stem Cells Dev, 16, 371, 10.1089/scd.2006.0037

Díaz-Cruz, 2005, Cyclooxygenase inhibitors suppress aromatase expression and activity in breast cancer cells., J Clin Endocrinol Metab, 90, 2563, 10.1210/jc.2004-2029

Ohno, 2004, A novel nonradioactive method for measuring aromatase activity using a human ovarian granulosa-like tumor cell line and an estrone ELISA., Toxicol Sci, 82, 443, 10.1093/toxsci/kfh292

Trösken, 2006, Inhibition of human CYP19 by azoles used as antifungal agents and aromatase inhibitors, using a new LC-MS/MS method for the analysis of estradiol product formation., Toxicology, 219, 33, 10.1016/j.tox.2005.10.020

Bradford, 1976, A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding., Anal Biochem, 72, 248, 10.1016/0003-2697(76)90527-3

Peng, 2004, Identification of a Functional vitamin D response element in the human insulin-like growth factor binding protein-3 promoter., Mol Endocrinol, 18, 1109, 10.1210/me.2003-0344

Hershberger, 1999, 1,25-Dihydroxycholecalciferol (1,25-D3) inhibits the growth of squamous cell carcinoma and down-modulates p21(Waf1/Cip1) in vitro and in vivo., Cancer Res, 59, 2644

Hershberger, 2001, Calcitriol (1,25-dihydroxycholecalciferol) enhances paclitaxel antitumor activity in vitro and in vivo and accelerates paclitaxel-induced apoptosis., Clin Cancer Res, 7, 1043

Tallarida, 2002, The interaction index: a measure of drug synergism., Pain, 98, 163, 10.1016/S0304-3959(02)00041-6

Harada, 1993, Tissue-specific expression of the human aromatase cytochrome P-450 gene by alternative use of multiple exons 1 and promoters, and switching of tissue-specific exons 1 in carcinogenesis., Proc Natl Acad Sci USA, 90, 11312, 10.1073/pnas.90.23.11312

Zhou, 1999, Identification and characterization of a cAMP-responsive element in the region upstream from promoter 1.3 of the human aromatase gene., Arch Biochem Biophys, 371, 179, 10.1006/abbi.1999.1454

Welsh, 2002, Impact of the Vitamin D3 receptor on growth-regulatory pathways in mammary gland and breast cancer., J Steroid Biochem Mol Biol, 83, 85, 10.1016/S0960-0760(02)00277-7

Hughes, 1997, 1,25-Dihydroxyvitamin D3 regulates estrogen metabolism in cultured keratinocytes., Endocrinology, 138, 3711, 10.1210/endo.138.9.5406

Lou, 2005, Regulation of aromatase and 5α-reductase by 25-hydroxyvitamin D(3), 1α,25-dihydroxyvitamin D(3), dexamethasone and progesterone in prostate cancer cells., J Steroid Biochem Mol Biol, 94, 151, 10.1016/j.jsbmb.2005.01.024

Kinuta, 2000, Vitamin D is an important factor in estrogen biosynthesis of both female and male gonads., Endocrinology, 141, 1317, 10.1210/endo.141.4.7403

Yanase, 2001, Regulation of aromatase by nuclear receptors., J Steroid Biochem Mol Biol, 79, 187, 10.1016/S0960-0760(01)00161-3

Brian H, Bano G, Mason HD, Nussey SS, 1,25-Dihydroxyvitamin D3 has a direct effect on steroid production by human granulosa cells. Proc 192nd Annual Meeting of the Society for Endocrinology, London, UK, 2001 (Abstract P2-73)

Agarwal, 1995, Quantitative detection of alternatively spliced transcripts of the aromatase cytochrome P450 (CYP19) gene in aromatase-expressing human cells by competitive RT-PCR., Mol Cell Probes, 9, 453, 10.1006/mcpr.1995.0069

Agarwal, 1996, Use of alternative promoters to express the aromatase cytochrome P450 (CYP19) gene in breast adipose tissues of cancer-free and breast cancer patients., J Clin Endocrinol Metab, 81, 3843

Bulun, 2005, Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment., Pharmacol Rev, 57, 359, 10.1124/pr.57.3.6

Zhou, 1997, Gene regulation studies of aromatase expression in breast cancer and adipose stromal cells., J Steroid Biochem Mol Biol, 61, 273, 10.1016/S0960-0760(97)80023-4

Enjuanes, 2005, Functional analysis of the I. 3, I. 6, pII and I. 4 promoters of CYP19 (aromatase) gene in human osteoblasts and their role in vitamin D and dexamethasone stimulation., Eur J Endocrinol, 153, 981, 10.1530/eje.1.02032

Sun, 1998, Characterization of a region upstream of exon I. 1 of the human CYP19 (aromatase) gene that mediates regulation by retinoids in human choriocarcinoma cells., Endocrinology, 139, 1684, 10.1210/endo.139.4.5959

Jääskeläinen, 2005, Negative regulation of human parathyroid hormone gene promoter by vitamin D3 through nuclear factor Y., Biochem Biophys Res Commun, 328, 831, 10.1016/j.bbrc.2005.01.033

Koszewski, 2004, Suppression of the human parathyroid hormone promoter by vitamin D involves displacement of NF-Y binding to the vitamin D response element., J Biol Chem, 279, 42431, 10.1074/jbc.M407742200

Richards, 2002, Signaling pathways regulating aromatase and cyclooxygenases in normal and malignant breast cells., J Steroid Biochem Mol Biol, 80, 203, 10.1016/S0960-0760(01)00187-X

Brodie, 2001, Aromatase and COX-2 expression in human breast cancers., J Steroid Biochem Mol Biol, 79, 41, 10.1016/S0960-0760(01)00131-5

Brueggemeier, 1999, Correlation of aromatase and cyclooxygenase gene expression in human breast cancer specimens., Cancer Lett, 140, 27, 10.1016/S0304-3835(99)00050-6

Wolf, 2006, 15-Hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer., Cancer Res, 66, 7818, 10.1158/0008-5472.CAN-05-4368

Bulun, 1996, Distribution of aromatase P450 transcripts and adipose fibroblasts in the human breast., J Clin Endocrinol Metab, 81, 1273

Meng, 2001, 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

Zhou, 2001, Malignant breast epithelial cells stimulate aromatase expression via promoter II in human adipose fibroblasts: an epithelial-stromal interaction in breast tumors mediated by CCAAT/enhancer binding protein β., Cancer Res, 61, 2328

Price, 1992, Determination of aromatase cytochrome P450 messenger ribonucleic acid in human breast tissue by competitive polymerase chain reaction amplification., J Clin Endocrinol Metab, 74, 1247

Chen, 2007, Prostaglandin E(2) induces breast cancer related aromatase promoters via activation of p38 and c-Jun NH(2)-terminal kinase in adipose fibroblasts., Cancer Res, 67, 8914, 10.1158/0008-5472.CAN-06-4751

Vu, 1996, 1,25-Dihydroxyvitamin D induces lipoprotein lipase expression in 3T3-L1 cells in association with adipocyte differentiation., Endocrinology, 137, 1540, 10.1210/endo.137.5.8612483

Sjögren, 2009, Elevated aromatase expression in osteoblasts leads to increased bone mass without systemic adverse effects., J Bone Miner Res, 24, 1263, 10.1359/jbmr.090208

Khan QJ, Reddy PS, Kimler BF, Sharma P, Baxa SE, O'Dea AP, Klemp JR, Fabian CJ 2009 Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Res Treat 10. 1007/S 10549-009-0495-x

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Endocrinology

Tập 151 Số 1

32-42

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