-
1
-
-
0034673201
-
Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen plus progestin
-
Apigenin Prevents Development of Medroxyprogesterone Acetate-Accelerated 7,12-Dimethylbenz(a)anthracene-Induced Mammary Tumors in Sprague-Dawley Rats Benford Mafuvadze1, Indira Benakanakere1, Franklin R. López Pérez2, Cynthia Besch-Williford2, Mark R. Ellersieck3, and Salman M. Hyder1 Authors' Affiliations: 1Department of Biomedical Sciences and Dalton Cardiovascular Research Center, 2Department of Pathology, and 3Agriculture Experiment Station, University of Missouri, Columbia, Missouri Corresponding Author: Salman M. Hyder, Dalton Cardiovascular Research Center, University of Missouri, 134 Research Park Drive, Columbia, MO 65211. Phone: 573-882-1266; Fax: 573-884-4232; E-mail: hyders@missouri.edu The use of progestins as a component of hormone replacement therapy has been linked to an increase in breast cancer risk in postmenopausal women. We have previously shown that medroxyprogesterone acetate (MPA), a commonly administered synthetic progestin, increases production of the potent angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells, leading to the development of new blood vessels and tumor growth. We sought to identify nontoxic chemicals that would inhibit progestin-induced tumorigenesis. We used a recently developed progestin-dependent mammary cancer model in which tumors are induced in Sprague-Dawley rats by 7,12-dimethylbenz(a) anthracene (DMBA) treatment. The flavonoid apigenin, which we previously found to inhibit progestin-dependent VEGF synthesis in human breast cancer cells in vitro, significantly delayed the development of, and decreased the incidence and multiplicity of, MPA-accelerated DMBA-induced mammary tumors in this animal model. Whereas apigenin decreased the occurrence of such tumors, it did not block MPA-induced intraductal and lobular epithelial cell hyperplasia in the mammary tissue. Apigenin blocked MPA-dependent increases in VEGF, and suppressed VEGF receptor-2 (VEGFR-2) but not VEGFR-1 in regions of hyperplasia. No differences were observed in estrogen or progesterone receptor (ER/PR) levels, or the number of estrogen receptor-positive cells, within the mammary gland of MPA-treated animals administered apigenin, MPA-treated animals, and placebo treated animals. However, the number of progesterone receptor-positive cells was reduced in animals treated with MPA or MPA and apigenin compared with those treated with placebo. These findings suggest that apigenin has important chemopreventive properties for those breast cancers that develop in response to progestins. ©2011 AACR. doi: 10.1158/1940-6207.CAPR-10-0382
-
(2000)
J Natl Cancer Inst
, vol.92
, pp. 328-332
-
-
Ross, R.K.1
Paganini-Hill, A.2
Wan, P.C.3
Pike, M.C.4
-
2
-
-
0037125379
-
Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial
-
Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000;92:328-32.
-
(2002)
JAMA
, vol.288
, pp. 321-333
-
-
Rossouew, J.E.1
Anderson, G.L.2
Prentice, R.L.3
LaCroix, A.Z.4
Kooperberg, C.5
Stefanick, M.L.6
-
3
-
-
4844228689
-
Association of hormone replacement therapy to estrogen and progesterone receptor status in invasive breast carcinoma
-
Rossouew JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-33.
-
(2004)
Cancer
, vol.101
, pp. 1490-1500
-
-
Chen, W.Y.1
Hankinson, S.E.2
Schnitt, S.L.3
Rosner, B.A.4
Holmes, M.D.5
Colditz, G.A.6
-
4
-
-
77958138780
-
Writing group for Women's Health Initiative Investigators. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women
-
Chen WY, Hankinson SE, Schnitt SL, Rosner BA, Holmes MD, Colditz GA. Association of hormone replacement therapy to estrogen and progesterone receptor status in invasive breast carcinoma. Cancer 2004;101:1490-500.
-
(2010)
JAMA
, vol.304
, pp. 1719-1720
-
-
Chlebowski, R.T.1
Anderson, G.L.2
Gass, M.3
-
5
-
-
77958138780
-
Proliferative effects of combination estrogen and progesterone replacement therapy on the normal postmenopausal gland in a murine model
-
Chlebowski RT, Anderson GL, Gass M, et al. Writing group for Women's Health Initiative Investigators. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010;304:1719-20.
-
(2001)
Am J Obstet Gynecol
, vol.183
, pp. 1-14
-
-
Raafat, A.M.1
Hofseth, L.J.2
Haklan, S.Z.3
-
6
-
-
0030640821
-
Proliferation of breast epithelial cells in healthy women during the menstrual cycle
-
Raafat AM, Hofseth LJ, Haklan SZ. Proliferative effects of combination estrogen and progesterone replacement therapy on the normal postmenopausal gland in a murine model. Am J Obstet Gynecol 2001;183:1-14.
-
(1997)
Am J Obstet Gynecol
, vol.176
, pp. 123-128
-
-
Soderqvist, G.1
Isaksson, E.2
Von Schoultz, B.3
Carlstrom, K.4
Tani, E.5
Skoog, L.6
-
7
-
-
35448981411
-
Progestin-dependent progression of human breast tumor xenografts: A novel model for evaluating antitumor therapeutics
-
Soderqvist G, Isaksson E, Von Schoultz B, Carlstrom K, Tani E, Skoog L. Proliferation of breast epithelial cells in healthy women during the menstrual cycle. Am J Obstet Gynecol 1997;176:123-8.
-
(2007)
Cancer Res
, vol.67
, pp. 9929-9936
-
-
Liang, Y.1
Besch-Williford, C.2
Brekken, R.A.3
Hyder, S.M.4
-
8
-
-
77957723055
-
Synthetic progestins induce growth and metastasis of BT-474 human breast cancer xenografts in nude mice
-
Liang Y, Besch-Williford C, Brekken RA, Hyder SM. Progestin-dependent progression of human breast tumor xenografts: a novel model for evaluating antitumor therapeutics. Cancer Res 2007;67:9929-36.
-
(2010)
Menopause
, vol.17
, pp. 1040-1047
-
-
Liang, Y.1
Benakanakere, I.2
Besch-Williford, C.3
Hyder, R.S.4
Ellersierck, M.R.5
Hyder, S.M.6
-
9
-
-
0032005986
-
Progestin regulation of vascular endothelial growth factor in human breast cancer
-
Liang Y, Benakanakere I, Besch-Williford C, Hyder RS, Ellersierck MR, Hyder SM. Synthetic progestins induce growth and metastasis of BT-474 human breast cancer xenografts in nude mice. Menopause 2010;17:1040-7.
-
(1998)
Cancer Res
, vol.58
, pp. 392-395
-
-
Hyder, S.M.1
Murphy, L.2
Stancel, G.M.3
-
10
-
-
23044452790
-
Proliferation of endothelial and tumor epithelial cells by progestin-induced VEGF from human breast cancer cells: Paracrine and autocrine effects
-
Hyder SM, Murphy L, Stancel GM. Progestin regulation of vascular endothelial growth factor in human breast cancer. Cancer Res 1998;58:392-5.
-
(2005)
Endocrinol
, vol.146
, pp. 3632-3641
-
-
Liang, Y.1
Hyder, S.M.2
-
11
-
-
0036985699
-
Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: Therapeutic implications
-
Liang Y, Hyder SM. Proliferation of endothelial and tumor epithelial cells by progestin-induced VEGF from human breast cancer cells: paracrine and autocrine effects. Endocrinol 2005;146:3632-41.
-
(2002)
Semin Oncol
, vol.29
, pp. 10-14
-
-
Ferrara, N.1
-
13
-
-
78149284013
-
Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer
-
Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 2010;468:103-7.
-
(2010)
Nature
, vol.468
, pp. 98-102
-
-
Schramek, D.1
Leibbrandt, A.2
Sigl, V.3
Kenner, L.4
Pospisilik, J.A.5
Lee, H.J.6
-
14
-
-
51649125766
-
Progestins in hormone replacement therapies reactivate cancer stem cells in women with preexisting breast cancers: A hypothesis
-
Schramek D, Leibbrandt A, Sigl V, Kenner L, Pospisilik JA, Lee HJ, et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 2010;468:98-102.
-
(2008)
J Clin Endocrinol Metab
, vol.93
, pp. 3295-3298
-
-
Horwitz, K.B.1
Sartorius, C.A.2
-
15
-
-
33746076355
-
Natural and synthetic progestins accelerate 7,12-dimethylbenz(a) anthracene (DMBA)-initiated mammary tumors and increase angiogenesis in Sprague-Dawley rats
-
Horwitz KB, Sartorius CA. Progestins in hormone replacement therapies reactivate cancer stem cells in women with preexisting breast cancers: A hypothesis. J Clin Endocrinol Metab 2008;93:3295-8.
-
(2006)
Clin Cancer Res
, vol.12
, pp. 4062-4071
-
-
Benakanakere, I.1
Besch-Wiliford, C.2
Schnell, J.3
Brandt, S.4
Molinolo, A.5
Hyder, S.M.6
-
16
-
-
74549219394
-
Curcumin delays development of medroxyprogesterone acetate-accelerated 7,12-dimethybenz(a)anthracene-induced mammary tumors
-
Benakanakere I, Besch-Wiliford C, Schnell J, Brandt S, Molinolo A, Hyder SM. Natural and synthetic progestins accelerate 7,12-dimethylbenz(a)anthracene (DMBA)-initiated mammary tumors and increase angiogenesis in Sprague-Dawley rats. Clin Cancer Res 2006;12:4062-71.
-
(2010)
Menopause
, vol.17
, pp. 178-184
-
-
Carrol, C.E.1
Benakanakere, I.2
Besch-Williford, C.3
Ellersierck, M.R.4
Hyder, S.M.5
-
17
-
-
77956398263
-
Synthetic progestins differentially promote or prevent 7,12-dimethylbenz(a) anthracene-induced mammary tumors in Sprague-Dawley rats
-
Carrol CE, Benakanakere I, Besch-Williford C, Ellersierck MR, Hyder SM. Curcumin delays development of medroxyprogesterone acetate-accelerated 7,12-dimethybenz(a)anthracene-induced mammary tumors. Menopause 2010;17:178-84.
-
(2010)
Cancer Prev Res
, vol.3
, pp. 1157-1167
-
-
Benakanakere, I.1
Besch-Williford, C.2
Carroll, C.E.3
Hyder, S.M.4
-
18
-
-
34248226610
-
Apigenin and cancer chemoprevention: Progress, potential and promise
-
Benakanakere I, Besch-Williford C, Carroll CE, Hyder SM. Synthetic progestins differentially promote or prevent 7,12-dimethylbenz(a) anthracene-induced mammary tumors in Sprague-Dawley rats. Cancer Prev Res 2010;3:1157-67.
-
(2007)
Int J Oncol
, vol.30
, pp. 233-245
-
-
Patel, D.1
Shukla, S.2
Gupta, S.3
-
19
-
-
0034807826
-
Dietary agents in cancer prevention: Flavonoids and isoflavonoid
-
Patel D, Shukla S, Gupta S. Apigenin and cancer chemoprevention: Progress, potential and promise. Int J Oncol 2007;30:233-45.
-
(2001)
Pharmacol Ther
, vol.90
, pp. 157-177
-
-
Birt, D.F.1
Hendrich, S.2
Wang, W.3
-
20
-
-
0035812747
-
Selective growth-inhibitory, cell-cycle deregulatory and apoptotic response of apigenin in normal versus human prostate carcinoma cells
-
Birt DF, Hendrich S, Wang W. Dietary agents in cancer prevention: Flavonoids and isoflavonoid. Pharmacol Ther 2001;90:157-77.
-
(2001)
Biochem Biophys Res Commun
, vol.287
, pp. 914-920
-
-
Gupta, S.1
Afaq, F.2
Mukhtar, H.3
-
21
-
-
33646828739
-
Anti-proliferative effect of apigenin and its apoptotic induction in human Hep G2 cells
-
Gupta S, Afaq F, Mukhtar H. Selective growth-inhibitory, cell-cycle deregulatory and apoptotic response of apigenin in normal versus human prostate carcinoma cells. Biochem Biophys Res Commun 2001;287:914-20.
-
(2006)
Cancer Lett
, vol.237
, pp. 207-214
-
-
Chiang, L.-C.1
Lean, T.N.2
Lin, I.-C.3
Kuo, P.-L.4
Lin, C.-C.5
-
22
-
-
77957694977
-
Apigenin blocks induction of VEGF mRNA and protein in progestin-treated human breast cancer cells
-
Chiang Lien-Chai, Lean Teik Ng, Lin I-Cheng, Kuo Po-Lin, Lin Chun-Ching. Anti-proliferative effect of apigenin and its apoptotic induction in human Hep G2 cells. Cancer Lett 2006;237:207-14.
-
(2010)
Menopause
, vol.17
, pp. 1055-1063
-
-
Mafuvadze, B.1
Benakanakere, I.2
Hyder, S.M.3
-
23
-
-
0035874047
-
Pharmacological and endogenous progestins induce vascular endothelial growth factor expression in human breast cancer cells
-
Mafuvadze B, Benakanakere I, Hyder SM. Apigenin blocks induction of VEGF mRNA and protein in progestin-treated human breast cancer cells. Menopause 2010;17:1055-63.
-
(2001)
Int J Cancer
, vol.92
, pp. 469-473
-
-
Hyder, S.M.1
Chiappetta, C.2
Stancel, G.M.3
-
24
-
-
40349111004
-
Inhibition of proteasome activity by the dietary flavonoid apigenin is associated with growth inhibition in cultured breast cancer cells and xenografts
-
Hyder SM, Chiappetta C, Stancel GM. Pharmacological and endogenous progestins induce vascular endothelial growth factor expression in human breast cancer cells. Int J Cancer 2001;92:469-73.
-
(2007)
Breast Cancer Res
, vol.9
-
-
Chen, D.1
Landis-Piwowar, K.R.2
Chen, M.S.3
Dou, Q.P.4
-
25
-
-
0029791362
-
Medroxyprogesterone acetate accelerates the development and increases the incidence of mouse mammary tumors induced by dimethylbenzanthracene
-
Chen D, Landis-Piwowar KR, Chen MS, Dou QP. Inhibition of proteasome activity by the dietary flavonoid apigenin is associated with growth inhibition in cultured breast cancer cells and xenografts. Breast Cancer Res 2007;9:R80.
-
(1996)
Carcinogenesis
, vol.17
, pp. 2069-2072
-
-
Aldaz, C.M.1
Liao, Q.Y.2
LaBate, M.3
Johnston, D.A.4
-
26
-
-
13544269344
-
Ligand- and cell-specific effects of signal transduction pathway inhibitors on progestin-induced VEGF levels in human breast cancer cells
-
Aldaz CM, Liao QY, LaBate M, Johnston DA. Medroxyprogesterone acetate accelerates the development and increases the incidence of mouse mammary tumors induced by dimethylbenzanthracene. Carcinogenesis 1996;17:2069-72.
-
(2005)
Molecular Endocrinology
, vol.19
, pp. 312-326
-
-
Wu, J.1
Brandt, S.2
Hyder, S.M.3
-
27
-
-
0023926059
-
Regulation of progesterone receptor message ribonucleic acid and protein levels in MCF-7 cells by estradiol: Analysis of estrogen's effect on progesterone receptor synthesis and degradation
-
Wu J, Brandt S, Hyder S. M, Ligand- and cell-specific effects of signal transduction pathway inhibitors on progestin-induced VEGF levels in human breast cancer cells. Molecular Endocrinology 2005;19:312-26.
-
(1988)
Endocrinol
, vol.122
, pp. 935-944
-
-
Narduli, A.M.1
Greene, G.L.2
O'Malley, B.W.3
Katzenellenbogen, B.S.4
-
28
-
-
0018175970
-
Estrogen control of progesterone receptor in human breast cancer: Role of estradiol and antiestrogen
-
Narduli AM, Greene GL, O'Malley BW, Katzenellenbogen BS. Regulation of progesterone receptor message ribonucleic acid and protein levels in MCF-7 cells by estradiol: analysis of estrogen's effect on progesterone receptor synthesis and degradation. Endocrinol 1988;122:935-44.
-
(1978)
Endocrinol
, vol.103
, pp. 1742-1751
-
-
Horwitz, K.B.1
Koseki, Y.2
McGuire, W.L.3
-
29
-
-
18044380913
-
Inhibition of the 26S proteasome blocks progesterone receptor-dependent transcription through failed recruitment of RNA polymerase II
-
Horwitz KB, Koseki Y, McGuire WL. Estrogen control of progesterone receptor in human breast cancer: Role of estradiol and antiestrogen. Endocrinol 1978;103:1742-51.
-
(2005)
J Steroid Biochem Mol Biol
, vol.94
, pp. 337-346
-
-
Dennis, A.P.1
Lonard, D.M.2
Nawaz, Z.3
O'Malley, B.W.4
-
30
-
-
0037028207
-
β-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells
-
Dennis AP, Lonard DM, Nawaz Z, O'Malley BW. Inhibition of the 26S proteasome blocks progesterone receptor-dependent transcription through failed recruitment of RNA polymerase II. J Steroid Biochem Mol Biol 2005;94:337-46.
-
(2002)
Oncogene
, vol.21
, pp. 8414-8427
-
-
Jaiswal, A.S.1
Marlow, B.P.2
Gupta, N.3
Narayan, S.4
-
31
-
-
33646574281
-
The dietary flavonoid apigenin sensitizes malignant tumor cells to tumor necrosis factor-related apoptosis inducing ligands
-
Jaiswal AS, Marlow BP, Gupta N, Narayan S, β-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 2002;21:8414-27.
-
(2006)
Mol Cancer Ther
, vol.5
, pp. 945-951
-
-
Horinaka, M.1
Yoshida, T.2
Nakata, S.3
Wakada, M.4
Sakai, T.5
-
32
-
-
0035059767
-
Apigenin inhibits growth and induces G2/M arrest by modulating cyclin-CDK regulators and ERK MAP kinase activation in breast carcinoma cells
-
Horinaka M, Yoshida T, Nakata S, Wakada M, Sakai T. The dietary flavonoid apigenin sensitizes malignant tumor cells to tumor necrosis factor-related apoptosis inducing ligands. Mol Cancer Ther 2006;5:945-51.
-
(2001)
Anticancer Res
, vol.21
, pp. 413-420
-
-
Yin, F.1
Giuliano, A.E.2
Van Herle, A.J.3
-
33
-
-
33751101135
-
Sex-steroid regulation of vascular endothelial growth factor in breast cancer
-
Yin F, Giuliano AE, Van Herle AJ. Apigenin inhibits growth and induces G2/M arrest by modulating cyclin-CDK regulators and ERK MAP kinase activation in breast carcinoma cells. Anticancer Res 2001;21:413-20.
-
(2006)
End Relat Cancer
, vol.13
, pp. 667-687
-
-
Hyder, S.M.1
-
34
-
-
0028929803
-
Angiogenesis in cancer, vascular, rheumatoid and other disease
-
Hyder S.M. Sex-steroid regulation of vascular endothelial growth factor in breast cancer. End Relat Cancer 2006;13:667-87.
-
(1995)
Nat Med
, vol.1
, pp. 27-31
-
-
Folkman, J.1
-
35
-
-
77951730125
-
Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells
-
Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27-31.
-
(2010)
Clin Cancer Res
, vol.16
, pp. 2580-2590
-
-
Li, Y.1
Zhang, T.2
Korkaya, H.3
Liu, S.4
Lee, H.-F.5
Newman, B.6
Yu, Y.7
Clotheir, S.G.8
Schwartz, S.J.9
Wicha, M.S.10
Sun, D.11
-
36
-
-
77953388315
-
Progesterone induces adult mammary stem cell expansion
-
Li Y, Zhang T, Korkaya H, Liu S, Lee H-F, Newman B, Yu Y, Clotheir SG, Schwartz SJ, Wicha MS, Sun D. Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res 2010;16:2580-90.
-
Nature
, vol.465
, pp. 803-807
-
-
Joshi, P.A.1
Jackson, H.W.2
Beristain, A.G.3
Di Grappa, M.A.4
Mote, P.A.5
Clarke, C.L.6
-
37
-
-
33749671337
-
Impact of quercetin and EGCG on key elements of the Wnt pathway in human colon carcinoma cells
-
Joshi PA, Jackson HW, Beristain AG, Di Grappa MA, Mote PA, Clarke CL, et al. Progesterone induces adult mammary stem cell expansion. Nature 465:803-7.
-
(2006)
J Agric Food Chem
, vol.54
, pp. 7075-7082
-
-
Pahlke, G.1
Ngiewih, Y.2
Kern, M.3
Jakobs, S.4
Marko, D.5
Eisenbrand, G.6
-
38
-
-
0033867027
-
Estrogenic activity of flavonoids in mice. The importance of estrogen receptor distribution, metabolism and bioavailability
-
Pahlke G, Ngiewih Y, Kern M, Jakobs S, Marko D, Eisenbrand G. Impact of quercetin and EGCG on key elements of the Wnt pathway in human colon carcinoma cells. J Agric Food Chem 2006;54:7075-82.
-
(2000)
Food Chem Toxicol
, vol.38
, pp. 555-564
-
-
Breinholt, V.1
Hossaini, A.2
Svendsen, G.W.3
Brouwer, C.4
Nielsen, S.E.5
-
39
-
-
51049098742
-
Apigenin inhibits antiestrogen-resistant breast cancer cell growth through estrogen receptor-alpha-dependent and estrogen receptor-alpha- independent mechanisms
-
Breinholt V, Hossaini A, Svendsen GW, Brouwer C, Nielsen SE. Estrogenic activity of flavonoids in mice. The importance of estrogen receptor distribution, metabolism and bioavailability. Food Chem Toxicol 2000;38:555-64.
-
(2008)
Mol Cancer Ther
, vol.7
, pp. 2096-2108
-
-
Long, X.1
Fan, M.2
Bigsby, R.M.3
Nephew, K.P.4
-
40
-
-
33744828685
-
Bioavailability of apigenin from apiin-rich parsley in humans
-
Long X, Fan M, Bigsby RM, Nephew KP. Apigenin inhibits antiestrogen-resistant breast cancer cell growth through estrogen receptor-alpha-dependent and estrogen receptor-alpha-independent mechanisms. Mol Cancer Ther 2008;7:2096-108.
-
(2006)
Ann Nutr Metab
, vol.50
, pp. 167-172
-
-
Meyer, H.1
Bolarinwa, A.2
Wolfram, G.3
Linseisen, J.4
|