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Clinical and Translational Medicine
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Open Access 01-12-2017 | Research

Circulating microRNAs in patients with hormone receptor-positive, metastatic breast cancer treated with dovitinib

Authors: Narayan Shivapurkar, Eveline E. Vietsch, Erin Carney, Claudine Isaacs, Anton Wellstein

Published in: Clinical and Translational Medicine | Issue 1/2017

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Abstract

Background

Serial analysis of biomarkers in the circulation of patients undergoing treatment (“liquid biopsies”) can provide new insights into drug effects. In particular the analysis of cell-free, circulating nucleic acids such as microRNAs (miRs) can reveal altered expression patterns indicative of mechanism of drug action, cancer growth, and tumor–stroma interactions.

Results

Here we analyzed plasma miRs in patients with hormone receptor positive, metastatic breast cancer with prior disease progression during aromatase inhibitor therapy (n = 8) in a phase I/II trial with the multiple tyrosine kinase inhibitor dovitinib (TKI258). Plasma miR levels were measured by quantitative RT-qPCR before and after treatment with dovitinib. A candidate miR signature of drug response was established from a 379 miR screen for detectable plasma miRs as well as from the published literature. Changes in miR expression patterns and tumor sizes were compared. In this analysis we identified miR-21-5p, miR-100-5p, miR-125b-5p, miR-126-3p, miR-375 and miR-424-5p as potential indicators of a response to dovitinib. The altered expression patterns observed for the six circulating miRs separated patients with resistant disease from those with drug responsive disease. There was no relationship between adverse effects of dovitinib treatment and identifiable changes in miR patterns.

Conclusion

We conclude that changes in the expression patterns of circulating miRs can be indicators of drug responses that merit prospective studies for validation.
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Literature
1.
Krause DS, Van Etten RA (2005) Tyrosine kinases as targets for cancer therapy. N Engl J Med 353(2):172–187CrossRefPubMed
2.
Hojjat-Farsangi M (2014) Small-molecule inhibitors of the receptor tyrosine kinases: promising tools for targeted cancer therapies. Int J Mol Sci 15(8):13768–13801CrossRefPubMedPubMedCentral
3.
Weinstein IB, Joe AK (2006) Mechanisms of disease: oncogene addiction—a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 3(8):448–457CrossRefPubMed
4.
Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10(2):116–129CrossRefPubMed
5.
Park CK, Jung WH, Koo JS (2016) Expression of cancer-associated fibroblast-related proteins differs between invasive lobular carcinoma and invasive ductal carcinoma. Breast Cancer Res Treat 159(1):55–69CrossRefPubMed
6.
7.
Holdman XB, Welte T, Rajapakshe K, Pond A, Coarfa C, Mo Q et al (2015) Upregulation of EGFR signaling is correlated with tumor stroma remodeling and tumor recurrence in FGFR1-driven breast cancer. Breast Cancer Res 17:141CrossRefPubMedPubMedCentral
8.
Brown W, Tan L, Smith A, Gray NS, Wendt M (2016) Covalent targeting of fibroblast growth factor receptor inhibits metastatic breast cancer. Mol Cancer Ther. 15:2096–2106CrossRefPubMedPubMedCentral
9.
Lee SH, Lopes de Menezes D, Vora J, Harris A, Ye H, Nordahl L et al (2005) In vivo target modulation and biological activity of CHIR-258, a multitargeted growth factor receptor kinase inhibitor, in colon cancer models. Clin Cancer Res 11(10):3633–3641CrossRefPubMed
10.
Wan X (2014) Prostate cancer cell–stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases. Sci Transl Med 6:1–14CrossRef
11.
Angevin E, Lopez-Martin JA, Lin C-C, Gschwend JE, Harzstark A, Castellano D et al (2013) Phase I study of dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic renal cell carcinoma. Clin Cancer Res 19(5):1257–1268CrossRefPubMed
12.
Escudier B, Grunwald V, Ravaud A, Ou YC, Castellano D, Lin CC et al (2014) Phase II results of dovitinib (TKI258) in patients with metastatic renal cell cancer. Clin Cancer Res 20(11):3012–3022CrossRefPubMed
13.
Kim KB, Chesney J, Robinson D, Gardner H, Shi MM, Kirkwood JM (2011) Phase I/II and pharmacodynamic study of dovitinib (TKI258), an inhibitor of fibroblast growth factor receptors and VEGF receptors, in patients with advanced melanoma. Clin Cancer Res 17(23):7451–7461CrossRefPubMed
14.
André F, Bachelot T, Campone M, Dalenc F, Perez-Garcia JM, Hurvitz SA et al (2013) Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer. Clin Cancer Res 19(13):3693–3702CrossRefPubMed
15.
Rapisuwon S, Vietsch EE, Wellstein A (2016) Circulating biomarkers to monitor cancer progression and treatment. Comput Struct Biotechol J 14:211–222CrossRef
16.
Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T (2010) Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem 285(23):17442–17452CrossRefPubMedPubMedCentral
17.
Cortez MA, Bueso-Ramos C, Ferdin J, Lopez-Berestein G, Sood AK, Calin GA (2011) MicroRNAs in body fluids—the mix of hormones and biomarkers. Nat Rev Clin Oncol 8(8):467–477CrossRefPubMedPubMedCentral
18.
Kleivi Sahlberg K, Bottai G, Naume B, Burwinkel B, Calin GA, Borresen-Dale AL et al (2015) A serum microRNA signature predicts tumor relapse and survival in triple-negative breast cancer patients. Clin Cancer Res 21(5):1207–1214CrossRefPubMed
19.
Stuckrath I, Rack B, Janni W, Jager B, Pantel K, Schwarzenbach H (2015) Aberrant plasma levels of circulating miR-16, miR-107, miR-130a and miR-146a are associated with lymph node metastasis and receptor status of breast cancer patients. Oncotarget 6(15):13387–13401CrossRefPubMedPubMedCentral
20.
Eichelser C, Flesch-Janys D, Chang-Claude J, Pantel K, Schwarzenbach H (2013) Deregulated serum concentrations of circulating cell-free microRNAs miR-17, miR-34a, miR-155, and miR-373 in human breast cancer development and progression. Clin Chem 59(10):1489–1496CrossRefPubMed
21.
Madhavan D, Zucknick M, Wallwiener M, Cuk K, Modugno C, Scharpff M et al (2012) Circulating miRNAs as surrogate markers for circulating tumor cells and prognostic markers in metastatic breast cancer. Clin Cancer Res 18(21):5972–5982CrossRefPubMed
22.
Shivapurkar N, Weiner LM, Marshall JL, Madhavan S, Deslattes Mays A, Juhl H et al (2014) Recurrence of early stage colon cancer predicted by expression pattern of circulating microRNAs. PLoS ONE 9(1):e84686CrossRefPubMedPubMedCentral
23.
Kodahl AR, Zeuthen P, Binder H, Knoop AS, Ditzel HJ (2014) Alterations in circulating miRNA levels following early-stage estrogen receptor-positive breast cancer resection in post-menopausal women. PLoS ONE 9(7):e101950CrossRefPubMedPubMedCentral
24.
Muller V, Gade S, Steinbach B, Loibl S, von Minckwitz G, Untch M et al (2014) Changes in serum levels of miR-21, miR-210, and miR-373 in HER2-positive breast cancer patients undergoing neoadjuvant therapy: a translational research project within the Geparquinto trial. Breast Cancer Res Treat 147(1):61–68CrossRefPubMed
25.
Li Q, Liu M, Ma F, Luo Y, Cai R, Wang L et al (2014) Circulating miR-19a and miR-205 in serum may predict the sensitivity of luminal A subtype of breast cancer patients to neoadjuvant chemotherapy with epirubicin plus paclitaxel. PLoS ONE 9(8):e104870CrossRefPubMedPubMedCentral
26.
Bovy N, Blomme B, Freres P, Dederen S, Nivelles O, Lion M et al (2015) Endothelial exosomes contribute to the antitumor response during breast cancer neoadjuvant chemotherapy via microRNA transfer. Oncotarget 6(12):10253–10266CrossRefPubMedPubMedCentral
27.
Wang H, Tan G, Dong L, Cheng L, Li K, Wang Z et al (2012) Circulating MiR-125b as a marker predicting chemoresistance in breast cancer. PLoS ONE 7(4):e34210CrossRefPubMedPubMedCentral
28.
Jung EJ, Santarpia L, Kim J, Esteva FJ, Moretti E, Buzdar AU et al (2012) Plasma microRNA 210 levels correlate with sensitivity to trastuzumab and tumor presence in breast cancer patients. Cancer 118(10):2603–2614CrossRefPubMed
29.
LaConti JJ, Shivapurkar N, Preet A, Deslattes Mays A, Peran I, Kim SE et al (2011) Tissue and serum microRNAs in the Kras transgenic animal model and in patients with pancreatic cancer. PLoS ONE 6(6):e20687CrossRefPubMedPubMedCentral
30.
Zheng G, Wang H, Zhang X, Yang Y, Wang L, Du L et al (2013) Identification and validation of reference genes for qPCR detection of serum microRNAs in colorectal adenocarcinoma patients. PLoS ONE 8(12):e83025CrossRefPubMedPubMedCentral
31.
Rice J, Roberts H, Rai SN, Galandiuk S (2015) Housekeeping genes for studies of plasma microRNA: a need for more precise standardization. Surgery 158(5):1345–1351CrossRefPubMed
32.
Schwarzenbach H, Nishida N, Calin GA, Pantel K (2014) Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol. 11(3):145–156CrossRefPubMed
33.
Huo D, Clayton WM, Yoshimatsu TF, Chen J, Olopade OI (2016) Identification of a circulating MicroRNA signature to distinguish recurrence in breast cancer patients. Oncotarget 7(34):55231–55248CrossRefPubMedPubMedCentral
34.
Casey MC, Sweeney KJ, Brown JA, Kerin MJ (2016) Exploring circulating micro-RNA in the neoadjuvant treatment of breast cancer. Int J Cancer 139(1):12–22CrossRefPubMedPubMedCentral
35.
Vilquin P, Donini CF, Villedieu M, Grisard E, Corbo L, Bachelot T et al (2015) MicroRNA-125b upregulation confers aromatase inhibitor resistance and is a novel marker of poor prognosis in breast cancer. Breast Cancer Res 17:13CrossRefPubMedPubMedCentral
36.
Muramatsu F, Kidoya H, Naito H, Sakimoto S, Takakura N (2013) microRNA-125b inhibits tube formation of blood vessels through translational suppression of VE-cadherin. Oncogene 32(4):414–421CrossRefPubMed
37.
Chen H, Li L, Wang S, Lei Y, Ge Q, Lv N et al (2014) Reduced miR-126 expression facilitates angiogenesis of gastric cancer through its regulation on VEGF-A. Oncotarget 5(23):11873–11885CrossRefPubMedPubMedCentral
38.
Kong R, Ma Y, Feng J, Li S, Zhang W, Jiang J et al (2016) The crucial role of miR-126 on suppressing progression of esophageal cancer by targeting VEGF-A. Cell Mol Biol Lett 21:3CrossRefPubMedPubMedCentral
39.
Zhang Y, Yang P, Sun T, Li D, Xu X, Rui Y et al (2013) miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis. Nat Cell Biol 15(3):284–294CrossRefPubMedPubMedCentral
40.
Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos PD et al (2008) Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451(7175):147–152CrossRefPubMedPubMedCentral
41.
Saito Y, Friedman JM, Chihara Y, Egger G, Chuang JC, Liang G (2009) Epigenetic therapy upregulates the tumor suppressor microRNA-126 and its host gene EGFL7 in human cancer cells. Biochem Biophys Res Commun 379(3):726–731CrossRefPubMed
42.
Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M et al (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9(3):189–198CrossRefPubMed
43.
Wu X, Somlo G, Yu Y, Palomares MR, Li AX, Zhou W et al (2012) De novo sequencing of circulating miRNAs identifies novel markers predicting clinical outcome of locally advanced breast cancer. J Transl Med 10:42CrossRefPubMedPubMedCentral
44.
Mouillet JF, Donker RB, Mishima T, Cronqvist T, Chu T, Sadovsky Y (2013) The unique expression and function of miR-424 in human placental trophoblasts. Biol Reprod 89(25):1–9
45.
Petrelli A, Carollo R, Cargnelutti M, Iovino F, Callari M, Cimino D et al (2015) By promoting cell differentiation, miR-100 sensitizes basal-like breast cancer stem cells to hormonal therapy. Oncotarget 6(4):2315–2330CrossRefPubMed
46.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100(2):229–235CrossRefPubMed
Metadata
Title
Circulating microRNAs in patients with hormone receptor-positive, metastatic breast cancer treated with dovitinib
Authors
Narayan Shivapurkar
Eveline E. Vietsch
Erin Carney
Claudine Isaacs
Anton Wellstein
Publication date
01-12-2017
Publisher
Springer Berlin Heidelberg
Published in
Clinical and Translational Medicine / Issue 1/2017
Electronic ISSN: 2001-1326
DOI
https://doi.org/10.1186/s40169-017-0169-y

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