Front Oncol 10: 462

Osteoprotegerin: Relationship to Breast Cancer Risk and Prognosis

SNPs and Breast Cancer Risk

TNFRSF11B/OPG is a single copy gene located on chromosome 8q23-34, that spans 29 kb and consists of 5 exons (8). Studies on the OPG gene and breast cancer risk have focused on 3 SNPs – rs3102735, rs2073617, and rs2073618 (for all SNP annotations see https://www.ncbi.nlm.nih.gov/snp/). The rs3102735 SNP (major allele T, minor allele C) and rs2073617 SNP (major allele T, minor allele C) are in the 5′ promoter region of the OPG gene (9, 10). The rs2073618 OPG SNP (major allele G, minor allele C) is in the first exon of OPG with the minor allele C causing the third amino acid in the OPG protein to change from Lysine to Asparagine (11).

Ney et al. (12) studied the frequency of two OPG gene SNPs (rs3102735 and rs2073618) in 614 breast cancer patients and 784 healthy subjects. They found that the minor allele C of SNP rs3102735 was associated with a 1.5-fold increased risk for breast cancer. They did not find an association between the OPG gene SNP rs2073618 and breast cancer risk, but did establish that the major allele G was more likely to be found in invasive vs. non-invasive breast cancer cases (12). Ney et al. did not measure OPG protein serum levels, but studies on the same SNPs for different disease states did not find differences in OPG serum levels associated with SNPs rs3102735 or rs2073618 (13, 14).

A second group investigated associations of OPG gene SNPs rs2073618 and rs2073617 with breast cancer in 176 breast cancer patients and 100 healthy subjects. Unlike the study by Ney et al. described above, this study found that the SNP rs2073618 minor allele C was more frequent in breast cancer patients than in the control group (15). OPG serum levels in breast cancer patients and healthy subjects were not associated with SNP rs2073618 (15). An increased frequency of the major T allele in the OPG gene SNP rs2073617 was also observed in breast cancer patients as compared to the control group, again with no significant difference in OPG serum levels. These findings on SNPs rs2073618 and rs2073617 allele frequency and increased breast cancer risk were confirmed in a recent study of 115 breast cancer patients and 120 healthy subjects (16). In addition, a combined genotype of heterozygous for the GG major allele for OPG rs2073618 and the CC minor allele for OPG rs2073617 was shown to be protective against the breast cancer (16).

In summary, these studies demonstrate that OPG gene SNPs are associated with breast cancer risk (Table 1). The lack of differences in OPG serum levels would suggest that the effect of SNPs may be related to a change in protein activity, not expression level. However, additional studies on genotype and subsequent phenotype are required before conclusions can be drawn as to pro- or anti-tumor effects of OPG SNPs.

Table 1

Summary of studies regarding SNPs in the OPG gene and links to breast cancer.

Study	Genomic DNA from	SNP analysis and findings
Ney et al. (12)	614 breast cancer patients 784 healthy subjects	rs3102735- Minor C allele, 1.5x increased risk for breast cancer rs2073618- No association
Omar et al. (15) Shaker et al. (16)	176 breast cancer patients 100 healthy subjects 115 breast cancer patients 120 healthy subjects	rs2073618- Minor C allele more frequent in breast cancer patients rs2073617- Major T allele more frequent in breast cancer patients

OPG Protein Serum Levels and Breast Cancer Risk

OPG serum levels and breast cancer risk were initially examined in a large study which recruited 6,279 subjects (male and female) in Norway with no previous history of cancer (17). Serum samples were collected from each participant and frozen for the duration of the study (12 years) before measurement of OPG by ELISA. Nine hundred forty-eight participants developed cancer, of which 76 got breast cancer. Thirty cases of breast cancer were reported in the 1st Tertile of OPG serum group (0.46–2.78 ng/ml), 26 breast cancer cases for the 2nd Tertile of OPG serum group (2.79–3.55 ng/ml) and 20 breast cancer cases for the 3rd Tertile of OPG serum group (3.56–25.81 ng/ml). Based on this, it was calculated that women in the upper Tertile of serum OPG had a 45% lower relative risk of breast cancer compared to women in the 1st Tertile. Further analysis revealed that there was a 76% reduction in relative risk with high OPG levels when samples were analyzed in women below 60 years of age.

OPG expression vs. breast cancer risk has been analyzed in a more recent, similar type of study (18). The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort was a study designed to identify risk factors for cancer. From the 235,607 women who participated in this study, 2008 serum samples were analyzed for OPG expression from women who subsequently developed breast cancer alongside a group of matched healthy subjects. Of the 2008 cancer cases, 81% were Estrogen Receptor positive (ER+) and 19% were ER negative (ER–). The samples were organized into Tertiles based on the OPG serum levels determined at the start of the study before patients developed breast cancer: T1 = < 0.18 ng/ml, T2 = 0.18– < 0.22 ng/ml, and T3 = ≥ 0.22 ng/ml. Women with higher OPG serum levels had an increased relative risk (1.93) of risk for ER- breast cancer (T1–82, T2–78, T3–98 cases). There was a modest reduction in risk (0.84) of ER+ breast cancer with high OPG (T1–342, T2–297, T3–290 cases). When comparing these data with Vik et al. it appears that the range of OPG values are much lower in the Fortner et al. study (17, 18). The Vik et al. study. Tertiles look at OPG levels from 0.46 to 25.81 ng/ml while the Fortner et al. study looks at OPG levels from 0.18 ng/ml and below to above 0.22 ng/ml. The Fortner study reports a difference between ER+ and ER– samples, while ER status was not assigned in the Vik et al. study. Based on common findings, it is likely that the predominant subtype in 76 patients in the Vik et al. study would be ER+, and then there would be agreement in the association of low OPG serum levels with reduced risk for ER+ breast cancer (19).

In the only other study examining breast cancer risk, OPG serum levels were measured in a group of 278 postmenopausal women (20). The group was subsequently stratified as to whether they developed breast cancer within 12 months (40 women) or within 12–24 months (58 women), while the women that did not develop breast cancer during follow up were used as healthy subjects (180 women). Serum OPG levels ranged from 0.60–9.91 pM. There were no differences in serum OPG levels in the women who developed breast cancer within 12–24 months as compared to healthy subjects. However, in the group that developed breast cancer within 12 months, serum OPG levels were higher than in healthy subjects. It should be noted that tumor development in the 12 months prior to detection could lead to OPG protein production by tumor cells. Therefore, this data may not necessarily reflect OPG levels and “breast cancer risk”.

Another study followed up on women in the EPIC cohort who developed breast cancer and analyzed risk of death following a breast cancer diagnosis in relation to pre-diagnosis OPG serum levels and ER subtype in 2006 women (21). There was an increased risk of breast cancer-specific mortality in women with ER+ disease who had higher pre-diagnosis OPG serum levels (Quintile 5 > 12.38 pM as compared to Quintile 1 ≤ 7.80 pM). OPG levels were not associated with mortality risk in women with ER- breast cancer. Therefore, while the previous study by this group in the EPIC cohort linked high OPG with a slightly reduced risk for ER+ breast cancer, after breast cancer development, higher OPG levels correlate with poorer prognosis in this patient group.

OPG and Breast Cancer Risk With BRCA Mutations

RANKL plays a role in the breast cancer development signaling in patients with BRCA1 mutations (22). The ability of OPG to bind to RANKL and block its activity raised interest in the role of OPG in BRCA1-mutated breast cancer. Serum OPG levels were measured in 391 BRCA1 or−2 mutation carriers and 782 non-carrier healthy subjects. BRCA mutation carriers were found to have lower OPG serum levels than healthy subjects [range of values studied were 10.8 to 1,414 pg/ml (23)]. This study did not include a follow up to determine whether low OPG levels linked to breast cancer risk.

In a subsequent study, 206 women with BRCA1 or−2 mutations had serum OPG levels measured, were divided into low OPG (mean 62.9 pg/ml; range 4.2–94.5 pg/ml) or high OPG (mean 168.1 pg/ml; range 95.5–547.7 pg/ml) groups, and were followed for the development of breast cancer. Within 6.5 years, 13 of 103 women in the low OPG group developed breast cancer, compared with 6 of 103 women in the high OPG group (23). Overall, the women who developed breast cancer had lower baseline OPG serum levels (mean 90.59 pg/ml; range 4.2–205.7 pg/ml) compared to women who did not develop breast cancer (mean 117.9 pg/ml; range 7.4–547.7 pg/ml). The authors acknowledged that this was a small study, and that the effects observed were only marginally significant.

In summary, the limited studies in this area so far do not establish a clear link between OPG serum levels and breast cancer risk in BRCA mutation carriers. Additional studies are needed to establish whether these are indeed linked. The implications of these studies also need to be considered in light of the high breast cancer risk in this patient population.

In the studies on breast cancer risk we discussed, OPG expression was characterized as serum OPG levels. These studies are summarized in Table 2. In marked contrast, the studies that analyzed OPG expression in association with prognosis described below mainly consider OPG expression in the primary breast tumor.

Table 2

Summary of studies investigation associations between OPG and breast cancer risk.

Study	Participants	OPG Analysis	Significant data
Vik et al. (17)	76 women	Serum	Reduced breast cancer risk with high OPG expression
Kiechl et al. (20)	278 post-menopausal women	Serum	High OPG expression associated with breast cancer development within 12 months
Fortner et al. (18)	2008 women (EPIC cohort)	Serum	High OPG expression associated with increased risk for ER- breast cancer, suggestive inverse association for ER+
Sarink et al. (21)	2006 women (EPIC cohort)	Serum	High OPG expression associated with increased mortality in ER+ breast cancer
Widschwendter et al. (24)	391 BRCA1/2 mutation carriers 782 healthy subjects	Serum	BRCA mutation carriers had lower OPG expression
Oden et al. (23)	206 BRCA1/2 mutation carriers	Serum	Lower OPG expression in women that later developed breast cancer

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

^{Department of Medical Biology, Academic Medical Center Amsterdam, Amsterdam, Netherlands}

^{School of Medicine, California University of Science and Medicine, San Bernardino, CA, United States}

Edited by: Sercan Aksoy, Hacettepe University, Turkey

Reviewed by: Deniz Can Guven, Hacettepe University, Turkey; Nuriye Özdemir, Gazi University, Turkey

*Correspondence: Linda Connelly gro.msuc@lyllennoc

This article was submitted to Women's Cancer, a section of the journal Frontiers in Oncology

Edited by: Sercan Aksoy, Hacettepe University, Turkey

Reviewed by: Deniz Can Guven, Hacettepe University, Turkey; Nuriye Özdemir, Gazi University, Turkey

Received 2020 Jan 7; Accepted 2020 Mar 16.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract

Osteoprotegerin (OPG) is a secreted member of the Tumor Necrosis Factor (TNF) receptor superfamily (TNFRSF11B), that was first characterized and named for its protective role in bone remodeling. In this context, OPG binds to another TNF superfamily member Receptor Activator of NF-kappaB Ligand (RANKL; TNFSF11) and blocks interaction with RANK (TNFRSF11A), preventing RANKL/RANK stimulation of osteoclast maturation, and bone breakdown. Further studies revealed that OPG protein is also expressed by tumor cells and led to investigation of the role of OPG in tumor biology. An increasing body of data has demonstrated that OPG modulates breast tumor behavior. Initially, research was focused on OPG in the bone microenvironment as a potential inhibitor of RANKL-driven osteolysis. More recently, attention has shifted to include OPG expression and interactions in the primary breast tumor independent of RANKL. In the primary tumor, OPG may interact with another TNF superfamily member, TNF-Related Apoptosis Inducing Ligand (TRAIL; TNFSF10) to prevent apoptosis induction. Additional interest in OPG in breast cancer has been stimulated by the tumor-promoting role of its binding partner RANKL in association with BRCA1 gene mutations. We and others have previously summarized the functional studies on OPG and breast cancer (1, 2). After basic research studies on the in vitro role for OPG (and RANKL) in breast cancer, the field now expands to assess the in vivo role for OPG by examining the correlation between OPG expression and breast cancer risk or patient prognosis. However, the data reported so far is conflicting, since OPG expression appears linked to both good and poor patient survival. In the current review we will summarize these studies. Our goal is to provide stimulus for further research to bridge the basic research findings and clinical data regarding OPG in breast cancer.

Keywords: osteoprotegerin (OPG), TNFRSF11B, breast cancer, risk, prognosis, TNF superfamily

Abstract

Acknowledgments

DG dedicates this to Monique Keijzer for her courage and inspiration.

Acknowledgments

References

1. Goswami S, Sharma-Walia N. Osteoprotegerin rich tumor microenvironment: implications in breast cancer. Oncotarget. (2016) 7:42777–91. 10.18632/oncotarget.8658 ] [
2. Weichhaus M, Chung ST, Connelly L. Osteoprotegerin in breast cancer: beyond bone remodeling. Mol Cancer. (2015) 14:117. 10.1186/s12943-015-0390-5 ] [
3. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, et al. . Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. (1997) 89:309–19. 10.1016/S0092-8674(00)80209-3 [] [[PubMed]
4. Tsuda E, Goto M, Mochizuki S, Yano K, Kobayashi F, Morinaga T, et al. . Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun. (1997) 234:137–42. 10.1006/bbrc.1997.6603 [] [[PubMed]
5. Holen I, Cross SS, Neville-Webbe HL, Cross NA, Balasubramanian SP, Croucher PI, et al. . Osteoprotegerin (OPG) expression by breast cancer cells in vitro and breast tumours in vivo–a role in tumour cell survival?Breast Cancer Res Treat. (2005) 92:207–15. 10.1007/s10549-005-2419-8 [] [[PubMed]
6. Rachner TD, Benad P, Rauner M, Goettsch C, Singh SK, Schoppet M, et al. . Osteoprotegerin production by breast cancer cells is suppressed by dexamethasone and confers resistance against TRAIL-induced apoptosis. J Cell Biochem. (2009) 108:106–16. 10.1002/jcb.22232 [] [[PubMed]
7. Infante M, Fabi A, Cognetti F, Gorini S, Caprio M, Fabbri A. RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives. J Exp Clin Cancer Res. (2019) 38:12. 10.1186/s13046-018-1001-2 ] [
8. Morinaga T, Nakagawa N, Yasuda H, Tsuda E, Higashio K. Cloning and characterization of the gene encoding human osteoprotegerin/osteoclastogenesis-inhibitory factor. Eur J Biochem. (1998) 254:685–91. 10.1046/j.1432-1327.1998.2540685.x [] [[PubMed]
9. Arko B, Prezelj J, Komel R, Kocijancic A, Hudler P, Marc J. Sequence variations in the osteoprotegerin gene promoter in patients with postmenopausal osteoporosis. J Clin Endocrinol Metab. (2002) 87:4080–4. 10.1210/jc.2002-020124 [] [[PubMed]
10. Langdahl BL, Carstens M, Stenkjaer L, Eriksen EF. Polymorphisms in the osteoprotegerin gene are associated with osteoporotic fractures. J Bone Miner Res. (2002) 17:1245–55. 10.1359/jbmr.2002.17.7.1245 [] [[PubMed]
11. Zhao HY, Liu JM, Ning G, Zhao YJ, Zhang LZ, Sun LH, et al. . The influence of Lys3Asn polymorphism in the osteoprotegerin gene on bone mineral density in Chinese postmenopausal women. Osteoporos Int. (2005) 16:1519–24. 10.1007/s00198-005-1865-9 [] [[PubMed]
12. Ney JT, Juhasz-Boess I, Gruenhage F, Graeber S, Bohle RM, Pfreundschuh M, et al. . Genetic polymorphism of the OPG gene associated with breast cancer. BMC Cancer. (2013) 13:40. 10.1186/1471-2407-13-40 ] [
13. Bonfa AC, Seguro LP, Caparbo V, Bonfa E, Pereira RM. RANKL and OPG gene polymorphisms: associations with vertebral fractures and bone mineral density in premenopausal systemic lupus erythematosus. Osteoporos Int. (2015) 26:1563–71. 10.1007/s00198-015-3029-x [] [[PubMed]
14. Xue JB, Zhan XL, Wang WJ, Yan YG, Liu C. OPG rs2073617 polymorphism is associated with upregulated OPG protein expression and an increased risk of intervertebral disc degeneration. Exp Ther Med. (2016) 12:702–10. 10.3892/etm.2016.3342 ] [
15. Omar HS, Shaker OG, Nassar YH, Marzouk SA, ElMarzouky MS. The association between RANKL and osteoprotegerin gene polymorphisms with breast cancer. Mol Cell Biochem. (2015) 403:219–29. 10.1007/s11010-015-2352-z [] [[PubMed]
16. Shaker OG, Senousy MA. Association of SNP-SNP interactions between RANKL, OPG, CHI3L1, and VDR genes with breast cancer risk in Egyptian women. Clin Breast Cancer. (2019) 19:e220–e38. 10.1016/j.clbc.2018.09.004 [] [[PubMed]
17. Vik A, Brodin EE, Mathiesen EB, Brox J, Jorgensen L, Njolstad I, et al. . Serum osteoprotegerin and future risk of cancer and cancer-related mortality in the general population: the tromso study. Eur J Epidemiol. (2015) 30:219–30. 10.1007/s10654-014-9975-3 [] [[PubMed]
18. Fortner RT, Sarink D, Schock H, Johnson T, Tjonneland A, Olsen A, et al. . Osteoprotegerin and breast cancer risk by hormone receptor subtype: a nested case-control study in the EPIC cohort. BMC Med. (2017) 15:26. 10.1186/s12916-017-0786-8 ] [
19. Russnes HG, Lingjaerde OC, Borresen-Dale AL, Caldas C. Breast cancer molecular stratification: from intrinsic subtypes to integrative clusters. Am J Pathol. (2017) 187:2152–62. 10.1016/j.ajpath.2017.04.022 [] [[PubMed]
20. Kiechl S, Schramek D, Widschwendter M, Fourkala EO, Zaikin A, Jones A, et al. . Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer. Oncotarget. (2017) 8:3811–25. 10.18632/oncotarget.14013 ] [
21. Sarink D, Schock H, Johnson T, Chang-Claude J, Overvad K, Olsen A, et al. . Receptor activator of nuclear factor kB ligand, osteoprotegerin, and risk of death following a breast cancer diagnosis: results from the EPIC cohort. BMC Cancer. (2018) 18:1010. 10.1186/s12885-018-4887-3 ] [
22. Nolan E, Vaillant F, Branstetter D, Pal B, Giner G, Whitehead L, et al. . RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat Med. (2016) 22:933–9. 10.1038/nm.4118 [] [[PubMed]
23. Oden L, Akbari M, Zaman T, Singer CF, Sun P, Narod SA, et al. . Plasma osteoprotegerin and breast cancer risk in BRCA1 and BRCA2 mutation carriers. Oncotarget. (2016) 7:86687–94. 10.18632/oncotarget.13417 ] [
24. Widschwendter M, Burnell M, Fraser L, Rosenthal AN, Philpott S, Reisel D, et al. . Osteoprotegerin (OPG), the endogenous inhibitor of receptor activator of NF-κB ligand (RANKL), is dysregulated in BRCA mutation carriers. EBioMed. (2015) 2:1331–9. 10.1016/j.ebiom.2015.08.037 ] [
25. Cross SS, Harrison RF, Balasubramanian SP, Lippitt JM, Evans CA, Reed MW, et al. . Expression of receptor activator of nuclear factor kappabeta ligand (RANKL) and tumour necrosis factor related, apoptosis inducing ligand (TRAIL) in breast cancer, and their relations with osteoprotegerin, oestrogen receptor, and clinicopathological variables. J Clin Pathol. (2006) 59:716–20. 10.1136/jcp.2005.030031 ] [
26. Van Poznak C, Cross SS, Saggese M, Hudis C, Panageas KS, Norton L, et al. . Expression of osteoprotegerin (OPG), TNF related apoptosis inducing ligand (TRAIL), and receptor activator of nuclear factor kappaB ligand (RANKL) in human breast tumours. J Clin Pathol. (2006) 59:56–63. 10.1136/jcp.2005.026534 ] [
27. Santini D, Schiavon G, Vincenzi B, Gaeta L, Pantano F, Russo A, et al. . Receptor activator of NF-kB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. PLoS ONE. (2011) 6:e19234. 10.1371/journal.pone.0019234 ] [
28. Owen S, Ye L, Sanders AJ, Mason MD, Jiang WG. Expression profile of receptor activator of nuclear-kappaB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) in breast cancer. Anticancer Res. (2013) 33:199–206. [[PubMed]
29. Sanger N, Ruckhaberle E, Bianchini G, Heinrich T, Milde-Langosch K, Muller V, et al. . OPG and PgR show similar cohort specific effects as prognostic factors in ER positive breast cancer. Mol Oncol. (2014) 8:1196–207. 10.1016/j.molonc.2014.04.003 ] [
30. Park HS, Lee A, Chae BJ, Bae JS, Song BJ, Jung SS. Expression of receptor activator of nuclear factor κ-B as a poor prognostic marker in breast cancer. J Surg Oncol. (2014) 110:807–12. 10.1002/jso.23737 [] [[PubMed]
31. Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al. . The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. (2017) 67:93–9. 10.3322/caac.21388 [] [[PubMed]
32. Labovsky V, Martinez LM, Davies KM, Garcia-Rivello H, Calcagno Mde L, Matas A, et al. . Association between ligands and receptors related to the progression of early breast cancer in tumor epithelial and stromal cells. Clin Br Cancer. (2015) 15:e13–21. 10.1016/j.clbc.2014.05.006 [] [[PubMed]
33. Labovsky V, Martinez LM, Davies KM, de Lujan Calcagno M, Garcia-Rivello H, et al. . Prognostic significance of TRAIL-R3 and CCR-2 expression in tumor epithelial cells of patients with early breast cancer. BMC Cancer. (2017) 17:280. 10.1186/s12885-017-3259-8 ] [
34. Luo P, Lu G, Fan LL, Zhong X, Yang H, Xie R, et al. . Dysregulation of TMPRSS3 and TNFRSF11B correlates with tumorigenesis and poor prognosis in patients with breast cancer. Oncol Rep. (2017) 37:2057–62. 10.3892/or.2017.5449 [] [[PubMed]
35. Vidula N, Yau C, Li J, Esserman LJ, Rugo HS. Receptor activator of nuclear factor kappa B (RANK) expression in primary breast cancer correlates with recurrence-free survival and development of bone metastases in I-SPY1 (CALGB 150007/15 ACRIN 6657). Br Cancer Res Treat. (2017) 165:129–38. 10.1007/s10549-017-4318-1 ] [
36. Timotheadou E, Kalogeras KT, Koliou GA, Wirtz RM, Zagouri F, Koutras A, et al. . Evaluation of the prognostic value of RANK, OPG, and RANKL mRNA expression in early breast cancer patients treated with anthracycline-based adjuvant chemotherapy. Transl Oncol. (2017) 10:589–98. 10.1016/j.tranon.2017.05.006 ] [
37. Rachner TD, Kasimir-Bauer S, Gobel A, Erdmann K, Hoffmann O, Browne A, et al. . Prognostic value of RANKL/OPG serum levels and disseminated tumor cells in nonmetastatic breast cancer. Clin Cancer Res. (2019) 25:1369–78. 10.1158/1078-0432.CCR-18-2482 [] [[PubMed]
38. Weichhaus M, Segaran P, Renaud A, Geerts D, Connelly L. Osteoprotegerin expression in triple-negative breast cancer cells promotes metastasis. Cancer Med. (2014) 3:1112–25. 10.1002/cam4.277 ] [
39. Chung ST, Geerts D, Roseman K, Renaud A, Connelly L. Osteoprotegerin mediates tumor-promoting effects of Interleukin-1beta in breast cancer cells. Mol Cancer. (2017) 16:27. 10.1186/s12943-017-0606-y ] [
40. Rachner TD, Schoppet M, Niebergall U, Hofbauer LC. 17beta-Estradiol inhibits osteoprotegerin production by the estrogen receptor-alpha-positive human breast cancer cell line MCF-7. Biochem Biophys Res Commun. (2008) 368:736–41. 10.1016/j.bbrc.2008.01.118 [] [[PubMed]
41. de Groot AF, Appelman-Dijkstra NM, van der Burg SH, Kroep JR. The anti-tumor effect of RANKL inhibition in malignant solid tumors - A systematic review. Cancer Treat Rev. (2018) 62:18–28. 10.1016/j.ctrv.2017.10.010 [] [[PubMed]
42. Yoldi G, Pellegrini P, Trinidad EM, Cordero A, Gomez-Miragaya J, Serra-Musach J, et al. . RANK signaling blockade reduces breast cancer recurrence by inducing tumor cell differentiation. Cancer Res. (2016) 76:5857–69. 10.1158/0008-5472.CAN-15-2745 [] [[PubMed]
43. Goswami S, Sharma-Walia N. Osteoprotegerin secreted by inflammatory and invasive breast cancer cells induces aneuploidy, cell proliferation and angiogenesis. BMC Cancer. (2015) 15:935. 10.1186/s12885-015-1837-1 ] [
44. Ottewell PD, Wang N, Brown HK, Fowles CA, Croucher PI, Eaton CL, et al. . OPG-Fc inhibits ovariectomy-induced growth of disseminated breast cancer cells in bone. Int J Cancer. (2015) 137:968–77. 10.1002/ijc.29439 [] [[PubMed]
45. Zinonos I, Luo KW, Labrinidis A, Liapis V, Hay S, Panagopoulos V, et al. . Pharmacologic inhibition of bone resorption prevents cancer-induced osteolysis but enhances soft tissue metastasis in a mouse model of osteolytic breast cancer. Int J Oncol. (2014) 45:532–40. 10.3892/ijo.2014.2468 ] [