Top

Published in:

Open Access 01-12-2017 | Research article

S100β as a serum marker in endocrine resistant breast cancer

Authors: Sara Charmsaz, Éamon Hughes, Fiona T. Bane, Paul Tibbitts, Marie McIlroy, Christopher Byrne, Sinéad Cocchiglia, Jean McBryan, Bryan T. Hennessy, Róisín M. Dwyer, Michael J. Kerin, Arnold D. Hill, Leonie S. Young

Published in: BMC Medicine | Issue 1/2017

Abstract

Background

Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer. However, its efficacy is limited by intrinsic and acquired resistance. Here the potential of S100β as a biomarker and inhibition of its signaling network as a therapeutic strategy in endocrine treated patients was investigated.

Methods

The expression of S100β in tissue and serum was assessed by immunohistochemistry and an enzyme-linked immunosorbent assay, respectively. The S100β signaling network was investigated in cell line models of endocrine resistance by western blot, PCR, immunoprecipitation, and chromatin-immunoprecipitation. Endocrine resistant xenografts and tumor explants from patients with resistant tumors were treated with endocrine therapy in the presence and absence of the p-Src kinase inhibitor, dasatinib.

Results

Tissue and serum levels of S100β were found to predict poor disease-free survival in endocrine-treated patients (n = 509, HR 2.32, 95% CI is 1.58–3.40, p < 0.0001 and n = 187, HR 4.009, 95% CI is 1.66–9.68, p = 0.002, respectively). Moreover, elevated levels of serum S100β detected during routine surveillance over the patient treatment period significantly associated with subsequent clinically confirmed disease recurrence (p = 0.019). In vivo studies demonstrated that endocrine treatment induced transcriptional regulation of S100β which was successfully disrupted with tyrosine kinase inhibition. In endocrine resistant xenografts and tumor explants from patients with endocrine resistant breast cancer, combined endocrine and dasatinib treatment reduced tumor proliferation and down-regulated S100β protein expression in comparison to endocrine treatment alone.

Conclusions

S100β has potential as a new surveillance tool for patients with ER-positive breast cancer to monitor ongoing response to endocrine therapy. Moreover, endocrine resistant breast cancer patients with elevated S100β may benefit from combined endocrine and tyrosine-kinase inhibitor treatment.

Trial registration

ClinicalTrials.gov, NCT01840293). Registered on 23 April 2013. Retrospectively registered.

Available only for authorised users

Doughty JC. A review of the BIG results: the Breast International Group 1-98 trial analyses. Breast. 2008;17 Suppl 1:S9–S14.CrossRefPubMed

Johnston SR. Enhancing endocrine therapy for hormone receptor-positive advanced breast cancer: cotargeting signaling pathways. J Natl Cancer Inst. 2015;107(10). doi: https://doi.org/10.1093/jnci/djv212.

McIlroy M, McCartan D, Early S, O Gaora P, Pennington S, Hill AD, Young LS. Interaction of developmental transcription factor HOXC11 with steroid receptor coactivator SRC-1 mediates resistance to endocrine therapy in breast cancer. Cancer Res. 2010;70(4):1585–94.CrossRefPubMed

deBlacam C, Byrne C, Hughes E, McIlroy M, Bane F, Hill AD, Young LS. HOXC11-SRC-1 regulation of S100beta in cutaneous melanoma: new targets for the kinase inhibitor dasatinib. Br J Cancer. 2011;105((1):118–23.CrossRef

Walsh CA, Qin L, Tien J, Young LS, Xu J. The function of steroid receptor coactivator-1 in normal tissues and cancer. Int J Biol Sci. 2012;8(4):470–85.CrossRefPubMedPubMedCentral

Zhang X, Hamada J, Nishimoto A, Takahashi Y, Murai T, Tada M, Moriuchi T. HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells. J Cell Mol Med. 2007;11(2):299–306.CrossRefPubMedPubMedCentral

Jiang WG, Watkins G, Douglas-Jones A, Mansel RE. Psoriasin is aberrantly expressed in human breast cancer and is related to clinical outcomes. Int J Oncol. 2004;25(1):81–5.PubMed

Zhao H, Wilkie T, Deol Y, Sneh A, Ganju A, Basree M, Nasser MW, Ganju RK. miR-29b defines the pro-/anti-proliferative effects of S100A7 in breast cancer. Mol Cancer. 2015;14:11.CrossRefPubMedPubMedCentral

Chung L, Phillips L, Lin MZ, Moore K, Marsh DJ, Boyle FM, Baxter RC. A novel truncated form of S100P predicts disease-free survival in patients with lymph node positive breast cancer. Cancer Lett. 2015;368(1):64–70.CrossRefPubMed

10.

Gebhardt C, Lichtenberger R, Utikal J. Biomarker value and pitfalls of serum S100B in the follow-up of high-risk melanoma patients. J Dtsch Dermatol Ges. 2016;14(2):158–64.PubMed

11.

Sedaghat F, Notopoulos A. S100 protein family and its application in clinical practice. Hippokratia. 2008;12(4):198–204.PubMedPubMedCentral

12.

Donato R, Cannon BR, Sorci G, Riuzzi F, Hsu K, Weber DJ, Geczy CL. Functions of S100 proteins. Curr Mol Med. 2013;13(1):24–57.CrossRefPubMedPubMedCentral

13.

Massarweh S, Schiff R. Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk. Endocr Relat Cancer. 2006;13 Suppl 1:S15–24.CrossRefPubMed

14.

Sen B, Johnson FM. Regulation of SRC family kinases in human cancers. J Signal Transduct. 2011;2011:865819.CrossRefPubMedPubMedCentral

15.

Shah YM, Rowan BG. The Src kinase pathway promotes tamoxifen agonist action in Ishikawa endometrial cells through phosphorylation-dependent stabilization of estrogen receptor (alpha) promoter interaction and elevated steroid receptor coactivator 1 activity. Mol Endocrinol. 2005;19(3):732–48.CrossRefPubMed

16.

Eustace AJ, Crown J, Clynes M, O’Donovan N. Preclinical evaluation of dasatinib, a potent Src kinase inhibitor, in melanoma cell lines. J Transl Med. 2008;6:53.CrossRefPubMedPubMedCentral

17.

Finn RS, Bengala C, Ibrahim N, Roche H, Sparano J, Strauss LC, Fairchild J, Sy O, Goldstein LJ. Dasatinib as a single agent in triple-negative breast cancer: results of an open-label phase 2 study. Clin Cancer Res. 2011;17(21):6905–13.CrossRefPubMed

18.

Mayer EL, Baurain JF, Sparano J, Strauss L, Campone M, Fumoleau P, Rugo H, Awada A, Sy O, Llombart-Cussac A. A phase 2 trial of dasatinib in patients with advanced HER2-positive and/or hormone receptor-positive breast cancer. Clin Cancer Res. 2011;17(21):6897–904.CrossRefPubMed

19.

Pusztai L, Moulder S, Altan M, Kwiatkowski D, Valero V, Ueno NT, Esteva FJ, Avritscher R, Qi Y, Strauss L, et al. Gene signature-guided dasatinib therapy in metastatic breast cancer. Clin Cancer Res. 2014;20(20):5265–71.CrossRefPubMed

20.

McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Statistics Subcommittee of the NCIEWGoCD: REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer. 2005;93(4):387–91.CrossRefPubMedPubMedCentral

21.

Dillon MF, Stafford AT, Kelly G, Redmond AM, McIlroy M, Crotty TB, McDermott E, Hill AD, Young LS. Cyclooxygenase-2 predicts adverse effects of tamoxifen: a possible mechanism of role for nuclear HER2 in breast cancer patients. Endocr Relat Cancer. 2008;15(3):745–53.CrossRefPubMed

22.

Centenera MM, Gillis JL, Hanson AR, Jindal S, Taylor RA, Risbridger GP, Sutherland PD, Scher HI, Raj GV, Knudsen KE, et al. Evidence for efficacy of new Hsp90 inhibitors revealed by ex vivo culture of human prostate tumors. Clin Cancer Res. 2012;18(13):3562–70.CrossRefPubMed

23.

McCartan D, Bolger JC, Fagan A, Byrne C, Hao Y, Qin L, McIlroy M, Xu J, Hill AD, Gaora P, et al. Global characterization of the SRC-1 transcriptome identifies ADAM22 as an ER-independent mediator of endocrine-resistant breast cancer. Cancer Res. 2012;72(1):220–9.CrossRefPubMed

24.

Bronzert DA, Greene GL, Lippman ME. Selection and characterization of a breast cancer cell line resistant to the antiestrogen LY 117018. Endocrinology. 1985;117(4):1409–17.CrossRefPubMed

25.

Redmond AM, Bane FT, Stafford AT, McIlroy M, Dillon MF, Crotty TB, Hill AD, Young LS. Coassociation of estrogen receptor and p160 proteins predicts resistance to endocrine treatment; SRC-1 is an independent predictor of breast cancer recurrence. Clin Cancer Res. 2009;15(6):2098–106.CrossRefPubMed

26.

McBryan J, Fagan A, McCartan D, Bane FT, Vareslija D, Cocchiglia S, Byrne C, Bolger J, McIlroy M, Hudson L, et al. Transcriptomic profiling of sequential tumors from breast cancer patients provides a global view of metastatic expression changes following endocrine therapy. Clin Cancer Res. 2015;21(23):5371–9.CrossRefPubMed

27.

Filipits M, Rudas M, Jakesz R, Dubsky P, Fitzal F, Singer CF, Dietze O, Greil R, Jelen A, Sevelda P, et al. A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors. Clin Cancer Res. 2011;17(18):6012–20.CrossRefPubMed

28.

Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27(8):1160–7.CrossRefPubMedPubMedCentral

29.

Nielsen TO, Parker JS, Leung S, Voduc D, Ebbert M, Vickery T, Davies SR, Snider J, Stijleman IJ, Reed J, et al. A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer. Clin Cancer Res. 2010;16(21):5222–32.CrossRefPubMedPubMedCentral

30.

Koren S, Bentires-Alj M. Breast tumor heterogeneity: source of fitness, hurdle for therapy. Mol Cell. 2015;60(4):537–46.CrossRefPubMed

31.

Saunus JM, Quinn MC, Patch AM, Pearson JV, Bailey PJ, Nones K, McCart Reed AE, Miller D, Wilson PJ, Al-Ejeh F, et al. Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance. J Pathol. 2015;237(3):363–78.CrossRefPubMed

32.

Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics. 2015;12(4):825–36.CrossRefPubMedPubMedCentral

33.

Pathiraja TN, Nayak SR, Xi Y, Jiang S, Garee JP, Edwards DP, Lee AV, Chen J, Shea MJ, Santen RJ, et al. Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer. Sci Transl Med. 2014;6(229):229ra241.CrossRef

34.

Daniel AR, Hagan CR, Lange CA. Progesterone receptor action: defining a role in breast cancer. Expert Rev Endocrinol Metab. 2011;6(3):359–69.CrossRefPubMedPubMedCentral

35.

Ankerst DP, Thompson IM. Sensitivity and specificity of prostate-specific antigen for prostate cancer detection with high rates of biopsy verification. Arch Ital Urol Androl. 2006;78(4):125–9.PubMed

Title: S100β as a serum marker in endocrine resistant breast cancer
Authors: Sara Charmsaz
Éamon Hughes
Fiona T. Bane
Paul Tibbitts
Marie McIlroy
Christopher Byrne
Sinéad Cocchiglia
Jean McBryan
Bryan T. Hennessy
Róisín M. Dwyer
Michael J. Kerin
Arnold D. Hill
Leonie S. Young
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: BMC Medicine / Issue 1/2017
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-017-0836-2

ACC 2024 Congress

Springer Medicine

S100β as a serum marker in endocrine resistant breast cancer

Abstract

Background

Methods

Results

Conclusions

Trial registration

ACC 2024 Congress

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2017

Mapping the evidence on pharmacological interventions for non-affective psychosis in humanitarian non-specialised settings: a UNHCR clinical guidance

The contribution of risk factors to socioeconomic inequalities in multimorbidity across the lifecourse: a longitudinal analysis of the Twenty-07 cohort

Expedited Partner Therapy (EPT) increases the frequency of partner notification among MSM in Lima, Peru: a pilot randomized controlled trial

Voluntarily stopping eating and drinking (VSED) to hasten death: may clinicians legally support patients to VSED?

Assessing the efficiency of catch-up campaigns for the introduction of pneumococcal conjugate vaccine: a modelling study based on data from PCV10 introduction in Kilifi, Kenya

Successes and failures: what did we learn from recent first-line treatment immunotherapy trials in non-small cell lung cancer?