Correlation of RANK and RANKL with mammographic density in primary breast cancer patients.
Breast cancer
Immunohistochemistry
Mammographic density
RANK expression
RANKL expression
Journal
Archives of gynecology and obstetrics
ISSN: 1432-0711
Titre abrégé: Arch Gynecol Obstet
Pays: Germany
ID NLM: 8710213
Informations de publication
Date de publication:
05 Jun 2024
05 Jun 2024
Historique:
received:
12
01
2024
accepted:
24
03
2024
medline:
5
6
2024
pubmed:
5
6
2024
entrez:
5
6
2024
Statut:
aheadofprint
Résumé
The receptor activator of nuclear factor kappa B (RANK) and its ligand (RANKL) have been shown to promote proliferation of the breast and breast carcinogenesis. The objective of this analysis was to investigate whether tumor-specific RANK and RANKL expression in patients with primary breast cancer is associated with high percentage mammographic density (PMD), which is a known breast cancer risk factor. Immunohistochemical staining of RANK and RANKL was performed in tissue microarrays (TMAs) from primary breast cancer samples of the Bavarian Breast Cancer Cases and Controls (BBCC) study. For RANK and RANKL expression, histochemical scores (H scores) with a cut-off value of > 0 vs 0 were established. PMD was measured in the contralateral, non-diseased breast. Linear regression models with PMD as outcome were calculated using common predictors of PMD (age at breast cancer diagnosis, body mass index (BMI) and parity) and RANK and RANKL H scores. Additionally, Spearman rank correlations (ρ) between PMD and RANK and RANKL H score were performed. In the final cohort of 412 patients, breast cancer-specific RANK and RANKL expression was not associated with PMD (P = 0.68). There was no correlation between PMD and RANK H score (Spearman's ρ = 0.01, P = 0.87) or RANKL H score (Spearman's ρ = 0.04, P = 0.41). RANK expression was highest in triple-negative tumors, followed by HER2-positive, luminal B-like and luminal A-like tumors, while no subtype-specific expression of RANKL was found. Results do not provide evidence for an association of RANK and RANKL expression in primary breast cancer with PMD.
Identifiants
pubmed: 38836929
doi: 10.1007/s00404-024-07495-1
pii: 10.1007/s00404-024-07495-1
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Breast Cancer Research Foundation
ID : BCRF-22-132
Organisme : California Breast Cancer Research Program
ID : BCRP 12IB-0155
Informations de copyright
© 2024. The Author(s).
Références
Rauh C, Hack CC, Haberle L et al (2012) Percent mammographic density and dense area as risk factors for breast cancer. Geburtshilfe Frauenheilkd 72(8):727–733
pubmed: 25258465
pmcid: 4168400
doi: 10.1055/s-0032-1315129
Boyd NF, Martin LJ, Bronskill M et al (2010) Breast tissue composition and susceptibility to breast cancer. J Natl Cancer Inst 102(16):1224–1237
pubmed: 20616353
pmcid: 2923218
doi: 10.1093/jnci/djq239
Martin LJ, Boyd NF (2008) Mammographic density Potential mechanisms of breast cancer risk associated with mammographic density: hypotheses based on epidemiological evidence. Breast Cancer Res. https://doi.org/10.1186/bcr1831
doi: 10.1186/bcr1831
pubmed: 18226174
pmcid: 3332634
Chen H, Fan S, Stone J et al (2022) Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci. Breast Cancer Res 24(1):27
pubmed: 35414113
pmcid: 9006574
doi: 10.1186/s13058-022-01524-0
Byrne C, Ursin G, Martin CF et al (2017) Mammographic density change with estrogen and progestin therapy and breast cancer risk. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djx001
doi: 10.1093/jnci/djx001
pubmed: 28376149
pmcid: 6005019
Hack CC, Emons J, Jud SM et al (2017) Association between mammographic density and pregnancies relative to age and BMI: a breast cancer case-only analysis. Breast Cancer Res Treat 166(3):701–708
pubmed: 28828694
doi: 10.1007/s10549-017-4446-7
Infante M, Fabi A, Cognetti F et al (2019) RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives. J Exp Clin Cancer Res 38(1):12
pubmed: 30621730
pmcid: 6325760
doi: 10.1186/s13046-018-1001-2
Ney JT, Fehm T, Juhasz-Boess I et al (2012) RANK, RANKL and OPG expression in breast cancer–influence on osseous metastasis. Geburtshilfe Frauenheilkd 72(5):385–391
pubmed: 25298541
pmcid: 4168338
doi: 10.1055/s-0031-1298276
Ono T, Hayashi M, Sasaki F et al (2020) RANKL biology: bone metabolism, the immune system, and beyond. Inflamm Regen 40:2
pubmed: 32047573
pmcid: 7006158
doi: 10.1186/s41232-019-0111-3
Gonzalez-Suarez E, Jacob AP, Jones J et al (2010) RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468(7320):103–107
pubmed: 20881963
doi: 10.1038/nature09495
Schramek D, Leibbrandt A, Sigl V et al (2010) Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 468(7320):98–102
pubmed: 20881962
pmcid: 3084017
doi: 10.1038/nature09387
Sigl V, Owusu-Boaitey K, Joshi PA et al (2016) RANKL/RANK control Brca1 mutation-driven mammary tumors. Cell Res 26(7):761–774
pubmed: 27241552
pmcid: 5129883
doi: 10.1038/cr.2016.69
Nolan E, Vaillant F, Branstetter D et al (2016) RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat Med 22(8):933–939
pubmed: 27322743
doi: 10.1038/nm.4118
Cadieux B, Coleman R, Jafarinasabian P et al (2022) Experience with denosumab (XGEVA(R)) for prevention of skeletal-related events in the 10 years after approval. J Bone Oncol 33:100416
pubmed: 35242510
pmcid: 8857591
doi: 10.1016/j.jbo.2022.100416
Untch M, Banys-Paluchowski M, Brucker SY, Budach W, Denkert C, Ditsch N, Fasching PA, Haidinger R, Heil J, Jackisch C, Janni W, Kolberg H-C, Krug D, Loibl S, Lüftner D, van Mackelenbergh M, Radosa JC, Reimer T, Welslau M, Würstlein R, Harbeck N, Huober J (2023) Treatment of early breast cancer: the 18th St. gallen international breast cancer consensus conference against the background of current German treatment recommendations. Geburtshilfe Frauenheilkd 83(9):1102–1116. https://doi.org/10.1055/a-2121-2495
doi: 10.1055/a-2121-2495
pubmed: 37706057
pmcid: 10497346
Lindeman GJ, Nolan E, Pal B et al (2016) Abstract P3–11–05 RANK ligand is a target for breast cancer prevention in BRCA1 mutation carriers. Cancer Res. https://doi.org/10.1038/nm.4118
doi: 10.1038/nm.4118
Bhulani N, Wood M, Tsai T et al (2022) A phase 3 study to determine the breast cancer risk reducing effect of denosumab in women carrying a germline BRCA1 mutation (BRCA-P Study). J Clin Oncol. https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS10616
doi: 10.1200/JCO.2022.40.16_suppl.TPS10616
Mintz R, Wang M, Xu S et al (2022) Hormone and receptor activator of NF-kappaB (RANK) pathway gene expression in plasma and mammographic breast density in postmenopausal women. Breast Cancer Res 24(1):28
pubmed: 35422057
pmcid: 9008951
doi: 10.1186/s13058-022-01522-2
Moran O, Zaman T, Eisen A et al (2018) Serum osteoprotegerin levels and mammographic density among high-risk women. Cancer Causes Control 29(6):507–517
pubmed: 29679262
doi: 10.1007/s10552-018-1035-y
Toriola AT, Appleton CM, Zong X et al (2018) Circulating Receptor Activator of Nuclear Factor-κB (RANK), RANK ligand (RANKL), and mammographic density in premenopausal women. Cancer Prev Res (Phila) 11(12):789–796
pubmed: 30352839
doi: 10.1158/1940-6207.CAPR-18-0199
Toriola AT, Dang HX, Hagemann IS et al (2017) Increased breast tissue receptor activator of nuclear factor-κB ligand (RANKL) gene expression is associated with higher mammographic density in premenopausal women. Oncotarget 8(43):73787–73792
pubmed: 29088745
pmcid: 5650300
doi: 10.18632/oncotarget.17909
Wöckel A., Festl J., Stüber T., et al. 2018. Interdisciplinary Screening, Diagnosis, Therapy and Follow-up of Breast Cancer Guideline of the DGGG and the DKG (S3-Level, AWMF Registry Number 032/045OL, December 2017) with Recommendations for the Screening, Diagnosis and Therapy of Breast Cancer. Geburtshilfe Frauenheilkd. https://doi.org/10.1055/a-0646-4522
Wunderle M, Gass P, Häberle L et al (2018) BRCA mutations and their influence on pathological complete response and prognosis in a clinical cohort of neoadjuvantly treated breast cancer patients. Breast Cancer Res Treat 171(1):85–94
pubmed: 29725888
doi: 10.1007/s10549-018-4797-8
Ursin G, Astrahan MA, Salane M et al (1998) The detection of changes in mammographic densities. Cancer Epidemiol Biomarkers Prev 7(1):43–47
pubmed: 9456242
Heusinger K, Jud SM, Haberle L et al (2012) Association of mammographic density with hormone receptors in invasive breast cancers: results from a case-only study. Int J Cancer 131(11):2643–2649
pubmed: 22392346
doi: 10.1002/ijc.27515
Haberle L, Fasching PA, Brehm B et al (2016) Mammographic density is the main correlate of tumors detected on ultrasound but not on mammography. Int J Cancer 139(9):1967–1974
pubmed: 27389655
doi: 10.1002/ijc.30261
Hack CC, Stoll MJ, Jud SM et al (2017) Correlation of mammographic density and serum calcium levels in patients with primary breast cancer. Cancer Med 6(6):1473–1481
pubmed: 28464481
pmcid: 5463083
doi: 10.1002/cam4.1066
Heindl F, Fasching PA, Hein A et al (2021) Mammographic density and prognosis in primary breast cancer patients. Breast 59:51–57
pubmed: 34157655
pmcid: 8237359
doi: 10.1016/j.breast.2021.06.004
Wood CE, Branstetter D, Jacob AP et al (2013) Progestin effects on cell proliferation pathways in the postmenopausal mammary gland. Breast Cancer Res 15(4):R62
pubmed: 23938070
pmcid: 3978455
doi: 10.1186/bcr3456
Pfitzner BM, Branstetter D, Loibl S et al (2014) RANK expression as a prognostic and predictive marker in breast cancer. Breast Cancer Res Treat 145(2):307–315
pubmed: 24737168
doi: 10.1007/s10549-014-2955-1
McCarty K.S., Jr., Miller L.S., Cox E.B. et al., 1985. Estrogen receptor analyses Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med. 109 (8) 716 721
Salmen J, Neugebauer J, Fasching PA et al (2014) Pooled analysis of the prognostic relevance of progesterone receptor status in five German cohort studies. Breast Cancer Res Treat 148(1):143–151
pubmed: 25253172
doi: 10.1007/s10549-014-3130-4
Wunderle M, Ruebner M, Haberle L et al (2020) RANKL and OPG and their influence on breast volume changes during pregnancy in healthy women. Sci Rep 10(1):5171
pubmed: 32198488
pmcid: 7083828
doi: 10.1038/s41598-020-62070-3
Kiechl S, Schramek D, Widschwendter M et al (2017) Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer. Oncotarget 8(3):3811–3825
pubmed: 28002811
doi: 10.18632/oncotarget.14013
Oden L, Akbari M, Zaman T et al (2016) Plasma osteoprotegerin and breast cancer risk in BRCA1 and BRCA2 mutation carriers. Oncotarget 7(52):86687–86694
pubmed: 27893411
pmcid: 5349945
doi: 10.18632/oncotarget.13417
Widschwendter M, Burnell M, Fraser L et al (2015) Osteoprotegerin (OPG), the endogenous inhibitor of receptor activator of NF-κB Ligand (RANKL), is dysregulated in BRCA mutation carriers. EBioMedicine 2(10):1331–1339
pubmed: 26629528
pmcid: 4634624
doi: 10.1016/j.ebiom.2015.08.037
Vik A, Brodin EE, Mathiesen EB et al (2015) Serum osteoprotegerin and future risk of cancer and cancer-related mortality in the general population: the Tromsø study. Eur J Epidemiol 30(3):219–230
pubmed: 25446307
doi: 10.1007/s10654-014-9975-3
Kotsopoulos J, McGee EE, Lozano-Esparza S et al (2020) Premenopausal plasma osteoprotegerin and breast cancer risk: a case-control analysis nested within the nurses’ health study II. Cancer Epidemiol Biomarkers Prev 29(6):1264–1270
pubmed: 32277005
pmcid: 7269832
doi: 10.1158/1055-9965.EPI-19-1154
Azim HA Jr, Peccatori FA, Brohee S et al (2015) RANK-ligand (RANKL) expression in young breast cancer patients and during pregnancy. Breast Cancer Res 17:24
pubmed: 25849336
pmcid: 4374174
doi: 10.1186/s13058-015-0538-7
Owen S, Ye L, Sanders AJ et al (2013) Expression profile of receptor activator of nuclear-κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) in breast cancer. Anticancer Res 33(1):199–206
pubmed: 23267146
Hu H, Wang J, Gupta A et al (2014) RANKL expression in normal and malignant breast tissue responds to progesterone and is up-regulated during the luteal phase. Breast Cancer Res Treat 146(3):515–523
pubmed: 25007964
doi: 10.1007/s10549-014-3049-9
Haynes BP, Viale G, Galimberti V et al (2014) Differences in expression of proliferation-associated genes and RANKL across the menstrual cycle in estrogen receptor-positive primary breast cancer. Breast Cancer Res Treat 148(2):327–335
pubmed: 25367875
doi: 10.1007/s10549-014-3181-6
Timotheadou E, Kalogeras KT, Koliou GA et al (2017) 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 10(4):589–598
pubmed: 28666187
pmcid: 5491451
doi: 10.1016/j.tranon.2017.05.006
Azim HA Jr, Michiels S, Bedard PL et al (2012) Elucidating prognosis and biology of breast cancer arising in young women using gene expression profiling. Clin Cancer Res 18(5):1341–1351
pubmed: 22261811
doi: 10.1158/1078-0432.CCR-11-2599
Behrens A, Wurmthaler L, Heindl F et al (2024) RANK and RANKL Expression in Tumors of Patients with Early Breast Cancer. Geburtshilfe Frauenheilkd 84(1):77–85
pubmed: 38178900
doi: 10.1055/a-2192-2998
Ciscar M, Trinidad EM, Perez-Chacon G et al (2023) RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer. EMBO Mol Med 15(4):e16715
pubmed: 36880458
pmcid: 10086586
doi: 10.15252/emmm.202216715
Reyes ME, Fujii T, Branstetter D et al (2017) Poor prognosis of patients with triple-negative breast cancer can be stratified by RANK and RANKL dual expression. Breast Cancer Res Treat 164(1):57–67
pubmed: 28417335
doi: 10.1007/s10549-017-4233-5
Vidula N, Yau C, Li J et al (2017) 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 150007/150012; ACRIN 6657). Breast Cancer Res Treat 165(1):129–138
pubmed: 28577080
pmcid: 5725604
doi: 10.1007/s10549-017-4318-1
Santini D, Schiavon G, Vincenzi B et al (2011) Receptor activator of NF-kB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. PLoS ONE 6(4):e19234
pubmed: 21559440
pmcid: 3084800
doi: 10.1371/journal.pone.0019234
Park HS, Lee A, Chae BJ et al (2014) Expression of receptor activator of nuclear factor kappa-B as a poor prognostic marker in breast cancer. J Surg Oncol 110(7):807–812
pubmed: 25111682
doi: 10.1002/jso.23737
Link T, Blohmer JU, Schmitt WD et al (2023) RANK expression as an independent predictor for response to neoadjuvant chemotherapy in luminal-like breast cancer: a translational insight from the geparX trial. Clin Cancer Res 29(22):4606–4612
pubmed: 37725572
doi: 10.1158/1078-0432.CCR-23-1801