Abstract
Estrogen deprivation (ED) either as a result of a natural or artificial menopause or the use of aromatase inhibitors in postmenopausal women results in a reduction of the incidence of breast cancer. Two major clinical trials of this approach comparing anastrozole or exemestane with placebo are currently in progress to test their efficacy for prevention. Reduction of contralateral breast lesions by at least 50% compared with tamoxifen indicate this approach has promise. The target lesion within the breast for ED is not known but we argue that hyperplastic enlarged lobular units (HELUs) as well as more advanced lesions are good candidates. A major problem for ED is de novo or acquired resistance to its effectiveness. We discuss potential mechanisms of resistance including high concentrations of tissue estrogens, increase in growth factor, and signal transduction pathways within the epithelial cell and activation of paracrine pathways from breast adipocytes, macrophages and fibroblasts. It may be possible to increase effectiveness of ED by additional preventive agents or by lifestyle alterations.
Keywords
- Breast Cancer
- Aromatase Inhibitor
- Contralateral Breast Cancer
- Postmenopausal Breast Cancer
- Mammary Gland Development
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Aharinejad S, Paulus P, Sioud M et al. (2004) Colony-stimulating factor-1 blockade by antisense oligonucleotides and small interfering RNAs suppress growth of human mammary tumor xenografts in mice. Cancer Res 64:5378–5384
Althuis MD, Fergenbum JH, Garcia-Closas M et al. (2004) Etiology of hormone receptor-defined breast cancer: a systematic review of the literature. Cancer Epidemiol Biomarkers Prev 13:1558–1568
Barcellos-Hoff MH, Medina D (2005) New highlights on stroma-epithelial interactions in breast cancer. Breast Cancer Res 7:33–36
Biswas DK, Singh S, Shi O et al. (2005) Crossroads of estrogen receptor and NF-kappaB signalling. Sci STKE 288:pe27
Blankenstein MA, Szymczak J, Daroszewski J et al. (1992) Estrogens in plasma and fatty tissue from breast cancer patients and women undergoing surgery for non-oncological reasons. Gynecol Endocrinol 6:13–17
Bocchinfuso WP, Korach KS (1997) Mammary gland development and tumorigenesis in estrogen receptor knockout mice. J Mammary Gland Biol Neoplasia 2:323–334
Bonney RC, Reed MJ, Davidson K et al. (1983) The relationship between 17 beta-hydroxysteroid dehydrogenase activity and oestrogen concentrations in human breast tumours and in normal breast tissue. Clin Endocrinol 19:727–739
Brisken C, Parks S, Vass T et al. (1998) A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc Natl Acad Sci U S A 95:5076–5081
Brisken C, Kaur S, Chavarria TE et al. (1999) Prolactin controls mammary gland development via direct and indirect mechanisms. Dev Biol 210:96–106
Catalano S, Mauro L, Marsico S et al. (2004) Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor alpha in MCF-7 cells. J Biol Chem 279:19908–19915
Chamras H, Bagga D, Elstner E et al. (1998) Preadipocytes stimulate breast cancer cell growth. Nutr Cancer 32:59–63
Chatterton RT Jr, Geiger AS, Mateo ET et al. (2004) Comparison of hormone levels in nipple aspirate fluid of pre and postmenopausal women: effect of oral contraceptives and hormone replacement. J Clin Endocrinol Metab 90:1686–1691
Chia K-S, Reilly M, Tan CS et al. (2005) Profound changes in breast cancer incidence may reflect changes into a westernized lifestyle: a comparative population-based study in Singapore and Sweden. Int J Cancer 113:302–306
Clarke RB, Howell A, Anderson E (1997a) Estrogen sensitivity of normal human breast tissue in vivo and implanted into athymic nude mice: analysis of the relationship between estrogen-induced proliferation and progesterone receptor expression. Breast Cancer Res Treat 45:121–133
Clarke RB, Howell A, Potten CS, Anderson E (1997b) Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res 57:4987–4991
Clarke RB, Anderson E, Howell A, Potten CS (2003) Regulation of human breast epithelial stem cells. Cell Prolif 36[Suppl 1]:45–58
Clarke RB, Spence K, Anderson E et al. (2005) A putative human breast stem cell population is enriched for steroid receptor-positive cells. Dev Biol 277:443–456
Cleary MP, Juneja SC, Philips SC et al. (2004) Leptin receptor-deficient MMTV-TGF-alpha/Lepr(db)Lepr(db) female mice do not develop oncogene-induced mammary tumors. Exp Biol Med (Maywood) 229:182–193
Clement K, Viguerie N, Poitou C et al. (2004) Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J 18:1657–1669
Cuzick J (2005) Aromatase inhibitors for breast cancer prevention. J Clin Oncol 23:1636–1643
Cuzick J, Powles T, Veronesi U et al. (2003) Overview of the main outcomes in breast cancer prevention trials. Lancet 361:296–300
Da Silva Correia J, Miranda Y, Austin-Brown N et al. (2006) Nod1-dependent control of tumor growth. Proc Natl Acad Sci U S A 103:1840–1845
De Graffenried LA et al. (2004) NF-kappa B inhibition markedly enhances sensitivity of resistant breast cancer tumor cells to tamoxifen. Ann Oncol 15:885–890
Dieudonne MN, Machinal-Quelin F, Serazin-Leroy V et al. (2002) Leptin mediates a proliferative response in human MCF7 breast cancer cells. Biochem Biophys Res Commun 293:622–628
Dobson RRH et al. (2000) The effects of prolonged HRT treatment in normal postmenopausal breast epithelium. Breast Cancer Res Treat 64:106
Dowsett M, Smith IE, Ebbs SR et al. (2006) Proliferation and apoptosis as markers of benefit in neo-adjuvant endocrine therapy of breast cancer. Clin Cancer Res 12:1024s–1030s
Eisen A, Lubinski J, Klijn J et al. (2005) Breast cancer risk following bilateral oophorectomy in BRCA1 and BRCA2 mutation carriers: an international case control study. J Clin Oncol 23:7491–7496
Ewan KB, Oketch-Rabah HA, Ravani SA et al. (2005) Proliferation of estrogen receptor-alpha-positive mammary epithelial cells is restrained by transforming growth factor-beta 1 in adult mice. Am J Pathol 167:409–417
Fechner RE (1972) Benign breast disease in women on estrogen therapy. Cancer 29:273–279
Feinleib M (1968) Breast cancer and artificial menopause: a cohort study. J Natl Cancer Inst 41:315–329
Frech MS, Halama ED, Tilli MT et al. (2005) Deregulated estrogen receptor α expression in mammary epithelial cells of transgenic mice results in the development of ductal carcinoma in-situ. Cancer Res 65:681–685
Garofalo C, Sisci D, Surmacz E (2004) Leptin interferes with the effects of the antiestrogen ICI 182,780 in MCF-7 breast cancer cells. Clin Cancer Res 10:6466–6475
Geisler J (2003) Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators. J Steroid Biochem Mol Biol 86:245–253
Hagemann T, Robinson SC, Schulz M et al. (2004) Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-alpha dependent up-regulation of matrix metalloproteases. Carcinogenesis 25:1543–1549
Hagemann T, Wilson J, Kulbe H et al. (2005) Macrophages induce invasiveness of epithelial cancer cells via NF-kB and JNK. J Immunol 175:1197–1205
Hardie DG (2005) New roles for the LKB1, AMPK pathway. Curr Opin Cell Biol 17:167–173
Harvie M, Howell A, Vierkant RA et al. (2005) Association of gain and loss of weight before and after menopause with risk of postmenopausal breast cancer in the IOWA women’s health study. Cancer Epidemiol Biomarkers Prev 14:656–661
Haslam SZ, Woodward TL (2003) Host microenvironment in breast cancer development: epithelial-cell-stromal-cell interactions and steroid hormone action in normal and cancerous mammary gland. Breast Cancer Res 5:208–215
Hirayama T, Wynder EL (1962) A study of the epidemiology of cancer of the breast II. The influence of hysterectomy. Cancer 5:28–38
Hofseth, Raafat AM, Osuch JR et al. (1999) Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab 84:4559–4565
Howell A (1989) Clinical evidence for the involvement of oestrogen in the development and progression of breast cancer. Proc R Soc Edin 95B:49–57
Howell A, Sims AH, Ong KR et al. (2005) Mechanisms of disease: prediction and prevention of breast cancer — cellular and molecular interactions. Nat Clin Prac Oncol 2:635–646
Hu X, Juneja SC, Maihle NJ, Cleary MP (2002) Leptin — a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst 94:1704–1711
Iyengar P, Combs TP, Shah SJ et al. (2003) Adipocyte-secreted factors synergistically promote mammary tumourigenesis through induction of anti-apoptotic transcriptional programs and proto-oncogene stabilisation. Oncogene 22:6408–6423
Iyengar P, Espina V, Williams TW et al. (2005) Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment. J Clin Invest 115:1163–1176
Jelovac D, Macedo L, Goloubeva OG et al. (2005) Additive antitumor effect of aromatase inhibitor letrozole and antiestrogen fulvestrant in a postmenopausal breast cancer model. Cancer Res 65:5439–5444
Johnston SR (2006) Clinical efforts to combine endocrine agents with targeted therapies against epidermal growth factor receptor/human epidermal growth factor receptor 2 and mammalian target of Rapamycin in breast cancer. Clin Cancer Res 12:1061s–1068s
Karagas MR (2000) Cancers of the female reproductive system. Menopause biology pathology. Academic Press, London, pp 359–365
Keith JC Jr, Albert LM, Leathurby Y et al. (2005) The utility of pathway selective estrogen receptor ligands that inhibit nuclear factor-kappa B transcriptional activity in models of rheumatoid arthritis. Arthritis Res Ther 7:R427–R438
Key TJ, Pike MC (1988) The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer. Eur J Cancer Clin Oncol 24:29–43
Kuperwasser C, Chavarria T, Wu M et al. (2004) Reconstruction of functionally normal and malignant human breast tissues in mice. Proc Natl Acad Sci U S A 101:4966–4971
Lee S et al. (2005a) Genetic alterations associated with early hyperplastic precursors of breast cancer. Breast Cancer Res Treat 94:24
Lee S et al. (2005b) Hormones, receptors and growth in hyperplastic enlarged lobular units: early potential precursors of breast cancer. Breast Cancer Res 8:1–9
Lin EY (2002) The macrophage growth factor CSF-1 in mammary gland development and tumor progression. J Mammary Gland Biol Neoplasia 7:147–162
Luetteke NC, Qiu TH, Fenton SE et al. (1999) Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development. Development 126:2739–2750
Mallepell S, Krust A, Chambon P, Brisken C (2006) Paracrine signaling through the epithelial estrogen receptor α is required for proliferation and morphogenesis in the mammary gland. Proc Natl Acad Sci U S A 103:2196–2201
Manabe Y, Toda S, Miyazaki K et al. (2003) Mature adipocytes, but not preadipocytes, promote the growth of breast carcinoma cells in collagen gel matrix culture through cancer-stromal cell interactions. J Pathol 201:221–228
Manson MM, Farmer PB, Gescher A et al. (2005) Innovative agents in cancer prevention. Recent Results Cancer Res 166:257–275
Martin L-A, Farmer I, Johnston SR et al. (2003) Enhanced estrogen receptor (ER) α, ERBB2 and MARK signal transduction pathways operate during the adaptation of MCF-7 cells to long-term estrogen deprivation. J Biol Chem 278:30458–30468
Martino S, Cauley JA, Barrett-Conner E et al. (2004) Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomised trial of raloxifene. J Natl Cancer Inst 96:1751–1761
Masamura S, Santner SJ, Heitjan DF, Santen RJ (1994) Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells. J Clin Endocrinol 80:2918–2925
McLeskey SW, Zhang L, El-Ashry D et al. (1998) Tamoxifen-resistant fibroblast growth factor-transfected MCF-7 cells are cross-resistant in vivo to the antiestrogen ICI 182,780 and two aromatase inhibitors. Clin Cancer Res 4:697–711
McTiernan A, Tworoger SS, Ulrich CM et al. (2004) Effect of exercise on serum estrogens in postmenopausal women: a 12 month randomised clinical trial. Cancer Res 64:2923–2928
Nakanishi C, Toi M (2005) Nuclear factor-kB inhibitors as sensitizers to anticancer drugs. Nat Rev 5:297–309
Okano H, Kawahara H, Toriya M et al. (2005) Function of RNA-binding protein Musashi-1 in stem cells. Exp Cell Res 306:349–356
Pasqualini JR, Chetrite G, Blacker C et al. (1996) Concentrations of estrone, estradiol and estrone sulfate and evaluation of sulfatase and aromatase activities in pre and postmenopausal breast cancer patients. J Clin Endocrinol Metab 81:1460–1464
Pike MC et al. (1997) A hormonal contraceptive approach to reducing breast and ovarian cancer risk: an update. Endocrinol Rel Cancer 4:125–133
Potten CS, Watson RJ, Williams GT et al. (1988) The effect of age and menstrual cycle upon proliferative activity of the normal human breast. Br J Cancer 58:163–170
Prasad R, Boland GP, Cramer A et al. (2003) Short term biologic response to withdrawal of hormone replacement therapy in patients with invasive breast carcinoma. Cancer 98:2539–2546
Rajala MW, Scherer PE (2003) Minireview: the adipocyte at the crossroads of energy homeostasis, inflammation and atherosclerosis. Endocrinology 144:3765–3773
Rayala SK, Hollander P, Balasenthil S et al. (2006) Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) interacts with PELPI and activates MAPK. J Biol Chem 281:4395–4403
Riggins RB, Zwart A, Nehra R, Clarke R (2005) The nuclear factor kappa B inhibitor parthenolide restores ICI 182,780 (Faslodex: fulvestrant)-induced apoptosis in antiestrogen-resistant breast cancer cells. Mol Cancer Ther 4:33–41
Rinaldi S, Key TJ, Peeters PH et al. (2005) Anthropometric measures, endogenous sex steroids and breast cancer risk in postmenopausal women: a study within the EPIC cohort. Int J Cancer 118:2832–2839
Rubio MF, Werbajh S, Cafferata EG et al. (2006) TNF-alpha enhances estrogen-induced cell proliferation of estrogen-dependent breast tumor cells through a complex containing nuclear factor-kappa B. Oncogene 25:1367–1377
Russo J, Ao X, Grill C, Russo IH (1999) Pattern of distribution of cells positive for estrogen receptor alpha and progesterone receptor in relation to proliferating cells in the mammary gland. Breast Cancer Res Treat 53:217–227
Sabnis GJ, Jelovac D, Long B, Brodie A (2005) The role of growth factor receptor pathways in human breast cancer cells adapted to long-term estrogen deprivation. Cancer Res 65:3903–3910
Shen Q, Brown PH (2003) Novel agents for the prevention of breast cancer: targeting transcription factors and signal transduction pathways. J Mammary Gland Biol Neoplasia 8:45–73
Shoker BS, Jarvis C, Clarke RB et al. (1999) Estrogen receptor-positive proliferating cells in the normal and precancerous breast. Am J Pathol 155:1811–1815
Shoker BS et al. (2000) Abnormal regulation of the estrogen receptor in benign breast lesions. J Clin Pathol 53:778–783
Sivaraman L, Hilsenbeck SG, Zhong L et al. (2001) Early exposure of the rat mammary gland to estrogen and progesterone blocks co-localisation of estrogen receptor expression and proliferation. J Endocrinol 171:75–83
Spicer DV, Pike MC (2000) Future possibilities in the prevention of breast cancer: luteinising hormone-releasing hormone agents. Breast Cancer Res 2:264–267
Stylianou S, Clarke RB, Brennan K (2006) Aberrant activation of notch signaling in human breast cancer. Cancer Res 66:1517–1525
Tekmal RR, Liu YG, Nair HB et al. (2005) Estrogen receptor alpha is required for mammary development and the induction of mammary hyperplasia and epigenetic alterations in the aromatase transgenic mice. J Steroid Biochem Mol Biol 95:9–15
Thomas DB (1993) Breast cancer in men. Epidemiol Rev 15:220–231
Thottassery JV, Sun Y, Westbrook L et al. (2004) Prolonged extracellular signal-regulated kinase 1/2 activation during fibroblast growth factor 1 or heregulin beta1-induced antiestrogen-resistant growth of breast cancer cells is resistant to mitogen-activated protein/extracellular regulated kinase kinase inhibitors. Cancer Res 64:4637–4647
Trichopoulos D, McMahon B, Cole P (1972) Menopause and breast cancer risk. J Natl Cancer Inst 48:605–613
Vadlamudi RK, Manavathi B, Balasenthil S et al. (2005) Functional implications of altered subcellular localization of PELP1 in breast cancer cells. Cancer Res 65:7724–7732
Wang S (2004) Recombinant cell ultrasensitive bioassay for measurement of estrogens in postmenopausal women. J Clin Endocrinol Metab 90:1407–1413
Weisberg SP, McCann D, Desai M et al. (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808
Wellings SR (1980) A hypothesis of the origin of human breast cancer from the terminal ductal lobular unit. Path Res Pract 166:515–535
Wellings SR, Jensen HM, Marcum RG (1975) An atlas of subgross pathology of the human breast with special reference to possible precancerous lesions. J Natl Cancer Inst 55:231–273
Wiesen JF, Young P, Werb Z, Cunha GR (1999) Signalling through the stromal epidermal growth factor receptor is necessary for mammary ductal development. Development 126:335–344
Yager JD, Davidson NE (2006) Estrogen carcinogenesis in breast cancer. N Eng J Med 354:270–282
Yasui Y, Potter JD (1999) The shape of age incidence curves of female breast cancer by hormone receptor status. Cancer Causes Control 10:431–437
Yin N, Wang D, Zhang H et al. (2004) Molecular mechanisms involved in the growth stimulation of breast cancer cells by leptin. Cancer Res 64:5870–5875
Zeps N (1996) Detection of a population of long-lived cells in mammary epithelium of the mouse. Cell Tissue Res 286:525–536
Zhang HZ, Bennett JM, Smith KG et al. (2002) Estrogen mediates mammary epithelial cell proliferation in serum-free culture indirectly via mammary stroma-derived hepatocyte growth factor. Endocrinology 143:3427–3434
Zhou Y, Eppenberger-Castori S, Marx C et al. (2005) Activation of nuclear factor-kappa B (NFkappaB) identifies a high-risk subset of hormone-dependent breast cancer. Int J Biochem Cell Biol 37:1130–1144
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2007 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Howell, A. et al. (2007). Estrogen Deprivation for Breast Cancer Prevention. In: Senn, HJ., Kapp, U. (eds) Cancer Prevention. Recent Results in Cancer Research, vol 174. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-37696-5_13
Download citation
DOI: https://doi.org/10.1007/978-3-540-37696-5_13
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-37695-8
Online ISBN: 978-3-540-37696-5
eBook Packages: MedicineMedicine (R0)