Forty years ago, the endocrine treatment for breast cancer was a last resort at palliation before the disease overwhelmed the patient (1). Ovarian ablation was the treatment of choice for the premenopausal patient, whereas either adrenalectomy or, paradoxically, high-dose synthetic estrogen therapy were used for treatment in postmenopausal patients. A reduction or an excess of estrogen provoked objective responses in one out of three women. Unfortunately, there was no way of predicting who would respond to endocrine ablation, and because so few patients responded there was no enthusiasm for developing new endocrine agents. All hopes for a cure for breast cancer turned to appropriate combinations of cytotoxic chemotherapy.
Today tamoxifen, a nonsteroidal antiestrogen (2), has proven to be effective in all stages of premenopausal and postmenopausal breast cancer, and several new endocrine strategies, including aromatase inhibitors, luteinizing-hormone releasing hormone (LHRH) superagonists, and a pure antiestrogen (fulvestrant), are now available for breast cancer treatment. Additionally, tamoxifen and raloxifene, a related compound, are used to reduce the risk of breast cancer and osteoporosis, respectively, in high-risk groups (3). Hormonal modulation and strategies to prevent the actions of estrogen in the breast are ubiquitous. However, with successful changes in treatment strategies comes the consequence of change.
This minireview will describe the current strategies for the treatment and prevention of breast cancer and present emerging new concepts about the consequences of exhaustive antiestrogen treatment on therapeutic resistance.
KennedyBJ. Hormone therapy for advanced breast cancer. Cancer18: 1551–1557, 1965.
2.
JordanVC. Tamoxifen: a most unlikely pioneering medicine. Nature Rev Drug Discov2: 205–213, 2003.
3.
JordanVC, MorrowM. Tamoxifen, raloxifene, and the prevention of breast cancer. Endocr Rev20: 253–278, 1999.
4.
JensenEV, JordanVC. The estrogen receptor: a model for molecular medicine. The Dorothy P. Landon AACR Prize for Translational Research. Clin Cancer Res9: 1980–1989, 2003.
5.
McGuireWL, CarbonePP, VollmerEP. Estrogen Receptors in Human Breast Cancer. New York: Raven Press, 1975.
6.
HarperMJ, WalpoleAL. A new derivative of triphenylethylene: effect on implantation and mode of action in rats. J Reprod Fertil13: 101–119, 1967.
7.
LemerLJ, JordanVC. The development of antiestrogens for the treatment of breast cancer: Eighth Cain Memorial Award Lecture. Cancer Res50: 4177–4189, 1990.
8.
ColeMP, JonesCT, ToddID. A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI 46474. Br J Cancer25: 270–275, 1971.
9.
JordanVC, KoernerS. Tamoxifen (ICI 46,474) and the human carcinoma 8S oestrogen receptor. Eur J Cancer11: 205–206, 1975.
10.
JordanVC, DowseLJ. Tamoxifen as an antitumour agent: effect on oestrogen binding. J Endocrinol68: 297–303, 1976.
11.
JordanVC, JaspanT. Tamoxifen as an antitumour agent: oestrogen binding as a predictive test for tumour response. J Endocrinol68: 453–460, 1976.
12.
JordanVC, AllenKE. Evaluation of the antitumour activity of the nonsteroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur J Cancer16: 239–251, 1980.
13.
MandlekarS, KongAN. Mechanisms of tamoxifen-induced apoptosis. Apoptosis6: 469–477, 2001.
14.
Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet354: 1451–1467, 1998.
15.
JordanVC. Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinomata. Eur J Cancer12: 419–424, 1976.
16.
FisherB, CostantinoJP, WickerhamDL, RedmondCK, KavanahM, CroninWM, VogelV, RobidouxA, DimitrovN, AtkinsJ, DalyM, WieandS, Tan-ChiuE, FordL, WolmarkN. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst90: 1371–1388, 1998.
17.
CuzickJ, PowlesT, VeronesiU, ForbesJ, EdwardsR, AshleyS, BoyleP. Overview of the main outcomes in breast-cancer prevention trials. Lancet361: 296–300, 2003.
18.
JordanVC, FritzNF, Langan-FaheyS, ThompsonM, TormeyDC. Alteration of endocrine parameters in premenopausal women with breast cancer during long-term adjuvant therapy with tamoxifen as the single agent. J Natl Cancer Inst83: 1488–1491, 1991.
19.
JakeszR, HausmaningerH, KubistaE, GnantM, MenzelC, BauernhoferT, SeifertM, HaiderM, MlineritschB, SteindorferP, KwasnyW, FridrikM, StegerG, WetteV, SamoniggH. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer—Austrian breast and colorectal cancer study group trial 5. J Clin Oncol15: 4621–4627, 2002.
20.
The ATAC Trialist Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomized trial. Lancet359: 2131–2139, 2002.
21.
FisherB, DignamJ, BryantJ, WolmarkN. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst93: 684–690, 2001.
22.
GossPE, IngleJN, MarinoS, RobertNJ, MussHB, PiccartMJ, CastiglioneM, TuD, ShepherdLE, PritchardKI, LivingstonRB, DavidsonNE, NortonL, PerezEA, AbramsJS, TherasseP, PalmerMJ, PaterJL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med349: 1–10, 2003.
23.
JordanVC. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. Part I: receptor interactions. J Med Chem46: 883–908, 2003.
24.
JordanVC. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines Part II: clinical considerations and new agents. J Med Chem46: 1082–1111, 2003.
25.
JordanVC. Selective estrogen receptor modulation: a personal perspective. Cancer Res61: 5683–5687, 2001.
26.
Barrett-ConnorE, GradyD. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health19: 55–72, 1998.
27.
FisherB, CostantinoJP, RedmondCK, FisherER, WickerhamDL, CroninWM. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst86: 527–537, 1994.
28.
EttingerB, BlackDM, MitlakBH, KnickerbockerRK, NickelsenT, GenantHK, ChristiansenC, DelmasPD, ZanchettaJR, StakkestadJ, GluerCC, KruegerK, CohenFJ, EckertS, EnsrudKE, AvioliLV, LipsP, CummingsSR. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators [see comments]. JAMA282: 637–645, 1999.
29.
CummingsSR, EckertS, KruegerKA, GradyD, PowlesTJ, CauleyJA, NortonL, NickelsenT, BjarnasonNH, MorrowM, LippmanME, BlackD, GlusmanJE, CostaA, JordanVC. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA281: 2189–2197, 1999.
30.
WalshBW, KullerLH, WildRA, PaulS, FarmerM, LawrenceJB, ShahAS, AndersonPW. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA279: 1445–1451, 1998.
31.
Barrett-ConnorE, GradyD, SashegyiA, AndersonPW, CoxDA, HoszowskiK, RautaharjuP, HarperKD. Raloxifene and cardiovascular events in osteoporotic postmenopausal women. JAMA287: 847–857, 2002.
32.
BenzCC, ScottGK, SarupJC, JohnsonRM, TripathyD, CoronadoE, ShepardHM, OsborneCK. Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat24: 85–95, 1993.
33.
OsborneCK, BardouV, HoppTA, ChamnessGC, HilsenbeckSG, FuquaSA, WongJ, AllredDC, ClarkGM, SchiffR. Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst95: 353–361, 2003.
34.
OsborneCK, HobbsK, ClarkGM. Effect of estrogens and antiestrogens on growth of human breast cancer cells in athymic nude mice. Cancer Res45: 584–591, 1985.
35.
DardesRC, MacGregor SchaferJ, Timm PearceS, OsipoC, ChenB, JordanVC. Regulation of estrogen target genes and growth by selective estrogen receptor modulators in endometrial cancer cells. Gynecol Oncol85: 498–506, 2002.
36.
SatyaswaroopPG, ZainoRJ, MortelR. Human endometrial adenocarcinoma transplanted into nude mice: growth regulation by estradiol. Science219: 58–60, 1983.
37.
GottardisMM, JordanVC. Development of tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. Cancer Res48: 5183–5187, 1988.
38.
MacGregor-SchaferJI, LeeES, O'reganRM, YaoK, JordanVC. Rapid development of tamoxifen stimulated mutant p53 breast tumors (T47D) in athymic mice. Clin Cancer Res6: 4373–4380, 2000.
39.
SatyaswaroopPG, ZainoRJ, MortelR. Estrogen-like effects of tamoxifen on human endometrial carcinoma transplanted into nude mice. Cancer Res44: 4006–4010, 1984.
40.
O'reganRM, GajdosC, DardesRC, De Los ReyesA, ParkW, RademakerAW, JordanVC. Effects of raloxifene after tamoxifen on breast and endometrial tumor growth in athymic mice. J Natl Cancer Inst94: 274–283, 2002.
41.
WijayaratneAL, McDonnellDP. The human estrogen receptor-alpha is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators. J Biol Chem276: 35684–35692, 2001.
42.
OsborneCK, Coronado-HeinsohnEB, HilsenbeckSG, McCueBL, WakelingAE, McClellandRA, ManningDL, NicholsonRI. Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer. J Natl Cancer Inst87: 746–750, 1995.
43.
LeeES, SchaferJM, YaoK, EnglandG, O'reganRM, De Los ReyesA, JordanVC. Cross-resistance of triphenylethylene-type antiestrogens but not ICI 182,780 in tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res6: 4893–4899, 2000.
44.
HowellA, DodwellDJ, AndersonH, RedfordJ. Response after withdrawal of tamoxifen and progestogens in advanced breast cancer [see comments]. Ann Oncol3: 611–617, 1992.
45.
BrodieA, LuQ, LongB. Aromatase and its inhibitors. J Steroid Biochem Mol Biol69: 205–210, 1999.
46.
BuzdarA. Exemestane in advanced breast cancer. Anticancer Drugs11: 609–616, 2000.
47.
GossPE, StrasserK. Aromatase inhibitors in the treatment and prevention of breast cancer. J Clin Oncol19: 881–894, 2001.
48.
HowellA, RobertsonJFR, Quaresma AlbanoJ, AschermannovaA, MauriacL, KleebergUR, VergotI, EriksteinB, WebsterA, MorrisC. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol20: 3396–3403, 2002.
49.
OsborneCK, PippenJ, JonesSE, ParkerLM, EllisM, ComeS, GertlerSZ, MayJT, BurtonG, DimeryI, WebsterA, MorrisC, ElledgeR, BuzdarA. J Clin Oncol Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol20: 3386–3395, 2002.
50.
WolfDM, JordanVC. A laboratory model to explain the survival advantage observed in patients taking adjuvant tamoxifen therapy. Recent Results Cancer Res127: 23–33, 1993.
51.
YaoK, LeeES, BentremDJ, EnglandG, SchaferJI, O'reganR, JordanVC. Antitumor action of physiological estradiol on tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res6: 2028–2036, 2000.
52.
GottardisMM, RobinsonSP, SatyaswaroopPG, JordanVC. Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res48: 812–815, 1988.
53.
MacGregor ShaferJI, LeeES, DardesRC, BentremDJ, O'reganRM, de los ReyesA, JordanVC. Analysis of cross-resistance of the selective estrogen receptor modulators arzoxifene (LY353381) and LY117018 in tamoxifen-stimulated breast cancer xenografts. Clin Cancer Res7: 2505–2512, 2001.
54.
OsipoC, GajdosC, LiuH, ChenB, JordanVC. Paradoxical action of fulvestrant on estradiol-induced regression of tamoxifen-stimulated breast cancer. J Natl Cancer Inst95: 1597–1607, 2003.
55.
ChisamoreMJ, AhmedY, BentremDJ, JordanVC, TonettiDA. Novel antitumor effect of estradiol in athymic mice injected with a T47D breast cancer cell line overexpressing protein kinase C alpha. Clin Cancer Res7: 3156–3165, 2001.
56.
JordanVC, OsipoC, MacGregor SchaferJ, FoxJE, ChengD, LiuH. Changing role of the oestrgoen receptor (ER) in the life and death of breast cancer. Breast12: 432–441, 2003.
57.
DardesRC, LiuH, GajdosC, O'reganR, de los ReyesA, JordanVC. Raloxifene stimulated endometrial cancer grown in athymic mice: cross resistance with ICI 182,780 and antitumor action of estradiol. Breast Cancer Res Treat69: 228 Abstract 447, 2001.
58.
SantenRJ, WorgulTJ, LiptonA, HarveyH, BoucherA, SamojlikE, WellsSA. Aminoglutethimide as treatment of postmenopausal women with advanced breast carcinoma. Ann Intern Med96: 94–101, 1982.
59.
WelshonsWV, JordanVC. Adaptation of estrogen-dependent MCF-7 cells to low estrogen (phenol red-free) culture. Eur J Cancer232: 1935–1939, 1987.
60.
KatzenellenbogenBS, KendraKL, NormanMJ, BerthoisY. Proliferation, hormonal responsiveness, and estrogen receptor content of MCF-7 human breast cancer cells grown in the short-term and long-term absence of estrogens. Cancer Res47: 4355–4360, 1987.
61.
JiangSY, WolfDM, YinglingJM, ChangC, JordanVC. An estrogen receptor positive MCF-7 clone that is resistant to antiestrogens and estradiol. Mol Cell Endocrinol90: 77–80, 1992.
62.
PinkJJ, JiangSY, FritschM, JordanVC. An estrogen-independent MCF-7 breast cancer cell line which contains a novel 80-kilodalton estrogen receptor-related protein. Cancer Res55: 2583–2590, 1995.
63.
SongRX, MorG, NaftolinF, McPhersonRA, SongJ, ZhangZ, YueW, WangJ, SantenRJ. Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17beta-estradiol. J Natl Cancer Inst93: 1714–1723, 2001.
64.
HaddowA, WatkinsonJM, PatersonmE. Influence of synthetic oestrogens upon advanced malignant disease. BMJ2: 393–398, 1944.
65.
IngleJN, AhmannDL, GreenSJ, EdmonsonJH, BiselHF, KvolsLK, NicholsWC, CreaganET, HahnRG, RubinJ, FrytakS. Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer. N Engl J Med304: 16–21, 1981.
66.
IngleJN. Estrogen as therapy for breast cancer. Breast Cancer Res4: 133–136, 2002.
67.
LonningPE, TaylorPD, AnkerG, IddonJ, WieL, JorgensenLM, MellaO, HowellA. High-dose estrogen treatment in postmenopausal breast cancer patients heavily exposed to endocrine therapy. Breast Cancer Res Treat67: 111–116, 2001.
68.
BlackLJ, JonesCD, FalconeJF. Antagonism of estrogen action with a new benzothiophene derived antiestrogen. Life Sci32: 1031–1036, 1983.
69.
JordanVC, CollinsMM, RowsbyL, PrestwichGA. monohydroxylated metabolite of tamoxifen with potent antiestrogenic activity. J Endocrinol75: 305–316, 1977.
70.
MacGregor SchaferJ, LiuH, BentremDJ, ZapfJW, JordanVC. Allosteric silencing of activating function 1 in the 4-hydroxytamoxifen estrogen receptor complex is induced by substituting glycine for aspartate at amino acid 351. Cancer Res60: 5097–5105, 2000.
71.
LiuH, ParkWC, BentremDJ, McKianKP, de los ReyesA, LowethJA, SchaferJM, ZapfJW, JordanVC. Structure-function relationships of the raloxifene-estrogen receptor-alpha complex for regulating transforming growth factor-alpha expression in breast cancer cells. J Biol Chem277: 9189–9198, 2002.
72.
NewmanSP, BatesNP, VernimmenD, ParkerMG, HurstHC. Cofactor competition between the ligand-bound oestrogen receptor and an intron 1 enhancer leads to oestrogen repression of ERBB2 expression in breast cancer. Oncogene19: 490–497, 2000.
73.
LiuH, LeeES, GajdosC, PearceST, ChenB, OsipoC, LowethJ, McKianK, De los ReyesA, WingL, JordanVC. Apoptotic action of 17 beta-estradiol in raloxifene resistant MCF-7 cells in vitro and in vivo. J Natl Cancer Inst95: 1586–1596, 2003.
74.
McDonnellDP, ClemmDL, HermannT, GoldmanME, PikeJW. Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Mol Endocrinol9: 659–669, 1995.
75.
JordanVC, MacGregor SchaferJI, LevensonAS, LiuH, PeaseKM, SimonsLA, ZapfJW. Molecular classification of estrogens. Cancer Res61: 6619–6623, 2001.
76.
GustR, KeilitzR, SchmidtK. Investigations of new lead structures for the design of selective estrogen receptor modulators. J Med Chem44: 1963–1970, 2001.
77.
BentremD, FoxJE, PearceST, LiuH, PappasS, KupferD, ZapfJW, JordanVC. Distinct molecular conformations of the estrogen receptor alpha complex exploited by environmental estrogens. Cancer Res63: 7490–7496, 2003.
78.
JordanVC, MittalS, GosdenB, KochR, LiebermanME. Structure-activity relationships of estrogens. Environmental Health Perspectives (NIH special issue)61: 97–110, 1985.
79.
LiuH, LeeES, De los ReyesA, ZapfJW, JordanVC. Silencing and reactivation of the selective estrogen receptor modulator-estrogen receptor alpha complex. Cancer Res61: 3632–3639, 2001.
80.
JiangSY, JordanVC. Growth regulation of estrogen receptor negative breast cancer cells transfected with cDNA's for estrogen receptor. J Natl Cancer Inst84: 580–591, 1992.
81.
LevensonAS, JordanVC. Transfection of human estrogen receptor (ER) cDNA in ER-negative mammalian cell lines. J Steroid Biochem Mol Biol51: 229–239, 1994.
