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Published in: Breast Cancer Research and Treatment 1/2017

01-01-2017 | Review

Can we prevent BRCA1-associated breast cancer by RANKL inhibition?

Authors: Joanne Kotsopoulos, Christian Singer, Steven A. Narod

Published in: Breast Cancer Research and Treatment | Issue 1/2017

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Abstract

BRCA1 mutation carriers face a high lifetime risk of breast cancer, estimated at 60 % compared to 10 % in the general population. BRCA1 breast cancers typically have an aggressive course (i.e., high-grade, triple-negative) and are associated with a poor prognosis. At present, primary prevention is limited to prophylactic removal of the unaffected breasts. Effective chemopreventive strategies are not yet available. Emerging evidence suggests that BRCA1 mutation carriers have high circulating levels of progesterone which may play a role in their susceptibility to breast cancer. Recently, the RANK/RANKL system was found to be dysregulated in women with a BRCA1 mutation. Mutation carriers had significantly lower endogenous levels of osteoprotegerin (OPG) than women without a BRCA1 mutation. OPG is an endogenous decoy receptor for RANKL and inhibits RANKL-mediated signaling. RANKL binds to RANK on mammary epithelial cells and stimulates their proliferation and maturation. Low OPG levels may contribute to mammary tumorigenesis through increased proliferation and may explain in part the increased breast cancer risk in BRCA1 mutation carriers. Denosumab is an anti-RANKL monoclonal antibody which is approved to treat osteoporosis and to prevent skeletal damage caused by bone metastases. The emerging role of aberrant RANK-signaling in BRCA1 tumorigenesis suggests that targeting of RANKL may prevent breast cancer among women with germline BRCA1 mutations. Clinical investigations of denosumab are warranted and may lead to a novel chemopreventive approach for breast cancer for high-risk women.
Literature
2.
3.
go back to reference Antoniou A et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72(5):1117–1130CrossRefPubMedPubMedCentral Antoniou A et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72(5):1117–1130CrossRefPubMedPubMedCentral
4.
go back to reference Da Silva L, Lakhani SR (2010) Pathology of hereditary breast cancer. Modern Pathol 23(Suppl 2):S46–S51CrossRef Da Silva L, Lakhani SR (2010) Pathology of hereditary breast cancer. Modern Pathol 23(Suppl 2):S46–S51CrossRef
5.
go back to reference Mavaddat N et al (2012) Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the consortium of investigators of modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomark Prev 21(1):134–147CrossRef Mavaddat N et al (2012) Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the consortium of investigators of modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomark Prev 21(1):134–147CrossRef
6.
go back to reference Chappuis PO, Nethercot V, Foulkes WD (2000) Clinico-pathological characteristics of BRCA1- and BRCA2-related breast cancer. Semin Surg Oncol 18(4):287–295CrossRefPubMed Chappuis PO, Nethercot V, Foulkes WD (2000) Clinico-pathological characteristics of BRCA1- and BRCA2-related breast cancer. Semin Surg Oncol 18(4):287–295CrossRefPubMed
7.
go back to reference Foulkes WD et al (2004) Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence of age, grade, and histological type. Clin Cancer Res 10(6):2029–2034CrossRefPubMed Foulkes WD et al (2004) Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence of age, grade, and histological type. Clin Cancer Res 10(6):2029–2034CrossRefPubMed
8.
go back to reference Lakhani SR et al (1998) Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90(15):1138–1145CrossRefPubMed Lakhani SR et al (1998) Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90(15):1138–1145CrossRefPubMed
9.
go back to reference Lakhani SR et al (2002) The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20(9):2310–2318CrossRefPubMed Lakhani SR et al (2002) The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20(9):2310–2318CrossRefPubMed
10.
go back to reference Robson ME (2002) Clinical considerations in the management of individuals at risk for hereditary breast and ovarian cancer. Cancer Control 9(6):457–465PubMed Robson ME (2002) Clinical considerations in the management of individuals at risk for hereditary breast and ovarian cancer. Cancer Control 9(6):457–465PubMed
11.
go back to reference Thompson D, Easton DF (2002) Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94(18):1358–1365CrossRefPubMed Thompson D, Easton DF (2002) Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94(18):1358–1365CrossRefPubMed
12.
go back to reference The Breast Cancer Linkage Consortium (1999) Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 91(15):1310–1316CrossRef The Breast Cancer Linkage Consortium (1999) Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 91(15):1310–1316CrossRef
13.
go back to reference Narod SA (2010) BRCA mutations in the management of breast cancer: the state of the art. Nat Rev Clin Oncol 7(12):702–707CrossRefPubMed Narod SA (2010) BRCA mutations in the management of breast cancer: the state of the art. Nat Rev Clin Oncol 7(12):702–707CrossRefPubMed
14.
go back to reference Lubinski J et al (2012) The risk of breast cancer in women with a BRCA1 mutation from North America and Poland. Int J Cancer 131(1):229–234CrossRefPubMed Lubinski J et al (2012) The risk of breast cancer in women with a BRCA1 mutation from North America and Poland. Int J Cancer 131(1):229–234CrossRefPubMed
15.
go back to reference Metcalfe K et al (2011) Risk of ipsilateral breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 127(1):287–296CrossRefPubMed Metcalfe K et al (2011) Risk of ipsilateral breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 127(1):287–296CrossRefPubMed
17.
go back to reference Hartmann LC et al (1999) Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 340(2):77–84CrossRefPubMed Hartmann LC et al (1999) Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 340(2):77–84CrossRefPubMed
18.
go back to reference Hartmann LC et al (2001) Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst 93(21):1633–1637CrossRefPubMed Hartmann LC et al (2001) Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst 93(21):1633–1637CrossRefPubMed
19.
go back to reference Rebbeck TR et al (2004) Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 22(6):1055–1062CrossRefPubMed Rebbeck TR et al (2004) Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 22(6):1055–1062CrossRefPubMed
20.
go back to reference Rebbeck TR (2002) Prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers. Eur J Cancer 38(Suppl 6):S15–S17CrossRefPubMed Rebbeck TR (2002) Prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers. Eur J Cancer 38(Suppl 6):S15–S17CrossRefPubMed
21.
go back to reference Kauff ND et al (2008) Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol 26(8):1331–1337CrossRefPubMedPubMedCentral Kauff ND et al (2008) Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol 26(8):1331–1337CrossRefPubMedPubMedCentral
22.
go back to reference Finch A et al (2006) Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 mutation. JAMA 296(2):185–192CrossRefPubMed Finch A et al (2006) Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 mutation. JAMA 296(2):185–192CrossRefPubMed
23.
go back to reference Finch AP et al (2014) Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol 32(15):1547–1553CrossRefPubMedPubMedCentral Finch AP et al (2014) Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol 32(15):1547–1553CrossRefPubMedPubMedCentral
24.
go back to reference Kotsopoulos J et al (2017) Bilateral oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 109(1):djw177CrossRefPubMed Kotsopoulos J et al (2017) Bilateral oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 109(1):djw177CrossRefPubMed
25.
go back to reference Narod SA et al (2000) Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case–control study. Hereditary breast cancer clinical study group. Lancet 356(9245):1876–1881CrossRefPubMed Narod SA et al (2000) Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case–control study. Hereditary breast cancer clinical study group. Lancet 356(9245):1876–1881CrossRefPubMed
26.
27.
go back to reference Gronwald J et al (2014) Duration of tamoxifen use and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 146(2):421–427CrossRefPubMedPubMedCentral Gronwald J et al (2014) Duration of tamoxifen use and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 146(2):421–427CrossRefPubMedPubMedCentral
28.
go back to reference Metcalfe KA et al (2008) International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers. Int J Cancer 122(9):2017–2022CrossRefPubMedPubMedCentral Metcalfe KA et al (2008) International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers. Int J Cancer 122(9):2017–2022CrossRefPubMedPubMedCentral
29.
go back to reference Metcalfe KA et al (2007) Variation in rates of uptake of preventive options by Canadian women carrying the BRCA1 or BRCA2 genetic mutation. Open Med 1(2):e92–e98PubMedPubMedCentral Metcalfe KA et al (2007) Variation in rates of uptake of preventive options by Canadian women carrying the BRCA1 or BRCA2 genetic mutation. Open Med 1(2):e92–e98PubMedPubMedCentral
30.
go back to reference Metcalfe KA et al (2014) Health care provider recommendations for reducing cancer risks among women with a BRCA1 or BRCA2 mutation. Clin Genet 85(1):21–30CrossRefPubMed Metcalfe KA et al (2014) Health care provider recommendations for reducing cancer risks among women with a BRCA1 or BRCA2 mutation. Clin Genet 85(1):21–30CrossRefPubMed
34.
go back to reference Fata JE et al (2000) The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103(1):41–50CrossRefPubMed Fata JE et al (2000) The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103(1):41–50CrossRefPubMed
35.
36.
go back to reference Gonzalez-Suarez E et al (2010) RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468(7320):103–107CrossRefPubMed Gonzalez-Suarez E et al (2010) RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468(7320):103–107CrossRefPubMed
37.
go back to reference Asselin-Labat ML et al (2010) Control of mammary stem cell function by steroid hormone signalling. Nature 465(7299):798–802CrossRefPubMed Asselin-Labat ML et al (2010) Control of mammary stem cell function by steroid hormone signalling. Nature 465(7299):798–802CrossRefPubMed
38.
go back to reference Joshi PA et al (2010) Progesterone induces adult mammary stem cell expansion. Nature 465(7299):803–807CrossRefPubMed Joshi PA et al (2010) Progesterone induces adult mammary stem cell expansion. Nature 465(7299):803–807CrossRefPubMed
39.
go back to reference Poole AJ et al (2006) Prevention of BRCA1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Science 314(5804):1467–1470CrossRefPubMed Poole AJ et al (2006) Prevention of BRCA1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Science 314(5804):1467–1470CrossRefPubMed
40.
go back to reference Joshi PA et al (2015) RANK signaling amplifies WNT-responsive mammary progenitors through R-SPONDIN1. Stem Cell Rep 5(1):31–44CrossRef Joshi PA et al (2015) RANK signaling amplifies WNT-responsive mammary progenitors through R-SPONDIN1. Stem Cell Rep 5(1):31–44CrossRef
41.
go back to reference Lim E et al (2009) Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 15(8):907–913CrossRefPubMed Lim E et al (2009) Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 15(8):907–913CrossRefPubMed
42.
go back to reference Nolan E et al (2016) RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat Med 22(8):933–939CrossRefPubMed Nolan E et al (2016) RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat Med 22(8):933–939CrossRefPubMed
44.
go back to reference Chlebowski RT et al (2013) Estrogen plus progestin and breast cancer incidence and mortality in the Women’s Health Initiative Observational Study. J Natl Cancer Inst 105(8):526–535CrossRefPubMedPubMedCentral Chlebowski RT et al (2013) Estrogen plus progestin and breast cancer incidence and mortality in the Women’s Health Initiative Observational Study. J Natl Cancer Inst 105(8):526–535CrossRefPubMedPubMedCentral
45.
go back to reference Anderson GL et al (2012) Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol 13(5):476–486CrossRefPubMedPubMedCentral Anderson GL et al (2012) Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol 13(5):476–486CrossRefPubMedPubMedCentral
46.
go back to reference Kotsopoulos J et al (2016) Hormone replacement therapy after menopause and risk of breast cancer in BRCA1 mutation carriers: a case–control study. Breast Cancer Res Treat 155(2):365–373CrossRefPubMed Kotsopoulos J et al (2016) Hormone replacement therapy after menopause and risk of breast cancer in BRCA1 mutation carriers: a case–control study. Breast Cancer Res Treat 155(2):365–373CrossRefPubMed
47.
go back to reference Widschwendter M et al (2015) Osteoprotegerin (OPG), the endogenous inhibitor of receptor activator of NF-kappaB ligand (RANKL), is dysregulated in BRCA mutation carriers. EBioMedicine 2(10):1331–1339CrossRefPubMedPubMedCentral Widschwendter M et al (2015) Osteoprotegerin (OPG), the endogenous inhibitor of receptor activator of NF-kappaB ligand (RANKL), is dysregulated in BRCA mutation carriers. EBioMedicine 2(10):1331–1339CrossRefPubMedPubMedCentral
48.
go back to reference Vik A et al (2015) Serum osteoprotegerin and future risk of cancer and cancer-related mortality in the general population: the Tromso study. Eur J Epidemiol 30(3):219–230CrossRefPubMed Vik A et al (2015) Serum osteoprotegerin and future risk of cancer and cancer-related mortality in the general population: the Tromso study. Eur J Epidemiol 30(3):219–230CrossRefPubMed
49.
go back to reference Mavaddat N et al (2013) Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst 105(11):812–822CrossRefPubMed Mavaddat N et al (2013) Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst 105(11):812–822CrossRefPubMed
50.
go back to reference Chlebowski RT et al (2015) Breast cancer after use of estrogen plus progestin and estrogen alone: analyses of data from 2 women’s health initiative randomized clinical trials. JAMA Oncol 1(3):296–305CrossRefPubMed Chlebowski RT et al (2015) Breast cancer after use of estrogen plus progestin and estrogen alone: analyses of data from 2 women’s health initiative randomized clinical trials. JAMA Oncol 1(3):296–305CrossRefPubMed
51.
go back to reference Gnant M et al (2015) Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 386(9992):433–443CrossRefPubMed Gnant M et al (2015) Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 386(9992):433–443CrossRefPubMed
52.
go back to reference Gnant MPG, Dubsky PC, Hubalek M, Greil R, Jakesz R, Wette V, Balic M, Haslbauer F, Melbinger-Zeinitzer E, Bjelic-Radisic V, Artner-Matuschek S, Fitzal F, Marth C, Sevelda P, Mlineritsch B, Steger GG, Manfreda D, Exner R, Egle D, Bergh J, Kainberger F, Warner D, Fesl C, Singer CF, On behalf of the Austrian Breast and Colorectal Cancer Study Group (2016) The impact of adjuvant denosumab on disease-free survival: results from 3425 postmenopausal patients of the ABCSG-18 trial. Cancer Res 76(Supplement 4):S2–02 Gnant MPG, Dubsky PC, Hubalek M, Greil R, Jakesz R, Wette V, Balic M, Haslbauer F, Melbinger-Zeinitzer E, Bjelic-Radisic V, Artner-Matuschek S, Fitzal F, Marth C, Sevelda P, Mlineritsch B, Steger GG, Manfreda D, Exner R, Egle D, Bergh J, Kainberger F, Warner D, Fesl C, Singer CF, On behalf of the Austrian Breast and Colorectal Cancer Study Group (2016) The impact of adjuvant denosumab on disease-free survival: results from 3425 postmenopausal patients of the ABCSG-18 trial. Cancer Res 76(Supplement 4):S2–02
Metadata
Title
Can we prevent BRCA1-associated breast cancer by RANKL inhibition?
Authors
Joanne Kotsopoulos
Christian Singer
Steven A. Narod
Publication date
01-01-2017
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2017
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-016-4029-z

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