Top

Published in:

01-01-2011 | Clinical trial

Vascular endothelial growth factor receptor 2 and downstream p38 mitogen-activated protein kinase are possible candidate markers of intrinsic resistance to adjuvant endocrine treatment in steroid receptor positive breast cancer

Authors: Barbro K. Linderholm, Henrik Hellborg, Ulla Johansson, Lambert Skoog, Janne Lehtiö

Published in: Breast Cancer Research and Treatment | Issue 2/2011

Abstract

A cross talk between tyrosine kinase receptors and mitogen-activated protein kinases (MAPKs) is proposed as involved in endocrine resistance. We wanted to investigate intratumoral levels of vascular endothelial growth factor receptor 2 (VEGFR2) and p38 MAPK in relation to relapse-free (RFS) and breast cancer corrected survival (BCCS) after adjuvant endocrine treatment, mainly tamoxifen for 2 or 5 years. We also wanted to investigate these markers in relation to early and late recurrences. VEGFR2 (n = 381) and p38 (n = 174) were determined by enzyme-linked immuno-sorbent assays in tumor homogenates from primary BC diagnosed 1993–1996. Wide ranges of VEGFR2 and p38 proteins were found; median 0.72 pg/μg DNA (range 0.0–11.66), and 0.04 pg/μg DNA (range 0.0–6.79), respectively. Detectable levels of p38 were registered in 65% and classified positive. Higher VEGFR2 were correlated to higher VEGF (P = 0.005), p38 MAPK (P = 0.018), negative ER (P = 0.008), larger tumors (P = 0.001), histopathological grade III (P = 0.018), distant metastasis (P = 0.044), shorter RFS (P = 0.013), and shorter BCCS (P = 0.017). Expression of p38 was significantly correlated with negative PgR (P = 0.044) and with early relapses (P = 0.021), while no difference was seen during the later follow-up period (P = 0.73). Higher VEGFR2 had a significant negative impact on both early (P = 0.029) and later recurrences (P = 0.018), while VEGF only predicted later relapses (P = 0.037). Our preliminary results suggest higher intratumoral levels of VEGFR2 and p38 MAPK as candidate markers of intrinsic resistance for adjuvant endocrine therapy.

Hanahan D, Weinberg R (2000) The hallmarks of cancer. Cell 100:57–70CrossRefPubMed

Guo P, Fang Q, Tao HQ, Schafer CA, Fenton BM, Ding I, Hu B, Cheng SY (2003) Overexpression of vascular endothelial growth factor by MCF-7 breast cancer cells promotes estrogen-independent tumor growth in vivo. Cancer Res 63:4684–4691PubMed

Kroll J, Waltenberger J (1999) A novel function of VEGF receptor-2 (KDR): rapid release of nitric oxide in response to VEGF-A stimulation in endothelial cells. Biochem Biophys Res Commun 265:636–639CrossRefPubMed

Aesoy R, Sanchez BC, Norum JH, Lewensohn R, Viktorsson K, Linderholm B (2008) An autocrine VEGF/VEGFR2 and p38 signaling loop confers resistance to 4-hydroxytamoxifen in MCF-7 breast cancer cells. Mol Cancer Res 10:1630–1638CrossRef

Folkman J (2003) Fundamental concepts of the angiogenic process. Curr Mol Med 3:643–651 ReviewCrossRefPubMed

Garrington TP, Johnson GL (1999) Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol 11:211–218 ReviewCrossRefPubMed

Fanger GR (1999) Regulation of the MAPK family members: role of subcellular localization and architectural organization. Histol Histopathol 14:887–894 ReviewPubMed

Kyriakis JM, Avruch J (2001) Mammalian Mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81:807–869PubMed

Rutqvist LE, Cedermark B, Fornander T, Glas U, Johansson H, Nordenskjöld B, Rotstein S, Skoog L, Somell A, Theve T et al (1989) The relationship between hormone receptor content and the effect of adjuvant tamoxifen in operable breast cancer. J Clin Oncol 7(10):1474–1484PubMed

10.

Cornier EM, Wolf MF, Jordan VC (1989) Decrease in estradiol-stimulated progesterone receptor production in MCF-7 cells by epidermal growth factor and possible clinical implication for paracrine-regulated breast cancer growth. Cancer Res 49:576–580

11.

Cui X, Zhang P, Deng W, Oesterreich S, Lu Y, Mills GB, Lee AV (2003) Insulin-like growth factor-I inhibits progesterone receptor expression in breast cancer cells via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway: progesterone receptor as a potential indicator of growth factor activity in breast cancer. Mol Endocrinol 17:575–588CrossRefPubMed

12.

Osipo C, Gajdos C, Cheng D, Jordan VC (2005) Reversal of tamoxifen resistant breast cancer by low dose estrogen therapy. J Steroid Biochem Mol Biol 93:249–256CrossRefPubMed

13.

Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, Come S, Gertler SZ, May JT, Burton G, Dimery I, Webster A, Morris C, Elledge R, Buzdar A (2002) Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 20:3386–3395CrossRefPubMed

14.

Howell A, Robertson JF, Quaresma Albano J, Aschermannova A, Mauriac L, Kleeberg UR, Vergote I, Erikstein B, Webster A, Morris C (2002) Fulvestrant, formerly ICI 182, 780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 20:3396–3403CrossRefPubMed

15.

Linderholm B, Bergqvist J, Hellborg H, Johansson U, Linderholm M, von Schoultz E, Elmberger G, Skoog L, Bergh J (2009) Shorter survival times following adjuvant endocrine therapy in oestrogen (ER)—and progesterone receptor (PgR) positive breast cancer (BC) overexpressing HER2 and/or with an increased expression of vascular endothelial growth factor (VEGF). Med Oncol 26:480–490CrossRefPubMed

16.

Linderholm BK, Hellborg H, Johansson U, Elmberger E, Skoog L, Lehtiö J, Lewensohn R (2009) Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple negative breast cancer. Ann Oncol 20:1639–1646CrossRefPubMed

17.

Geurts-Moespot J, Leake R, Benraad TJ, Sweep CG (2000) Twenty years of experience with the steroid receptor external quality assessment program—the paradigm for tumour biomarker EQA studies. On behalf of the EORTC Receptor and Biomarker Study Group. Int J Oncol 17:13–22 ReviewPubMed

18.

Linderholm B, Tavelin B, Grankvist K, Henriksson R (1998) Vascular endothelial growth factor is of high prognostic value in node-negative breast carcinoma. J Clin Oncol 16:3121–3131PubMed

19.

Linderholm B, Grankvist K, Wilking N, Johansson M, Tavelin B, Henriksson R (2000) Correlation of Vascular Endothelial Growth Factor (VEGF) and survival, metastasis sites and responsiveness to adjuvant systemic treatment in primary node-positive breast carcinoma. J Clin Oncol 18:1423–1431PubMed

20.

Foekens JA, Peters HA, Grebenchtchikov N, Look MP, Meijer-van Gelder ME, Geurts-Moespot A et al (2001) High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res 61:5407–5414PubMed

21.

Manders P, Beex LV, Tjan-Heijnen VC, Span PN, Sweep CG (2003) Vascular endothelial growth factor is associated with the efficacy of endocrine therapy in patients with advanced breast carcinoma. Cancer 98:2125–2132CrossRefPubMed

22.

McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics (2005) Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 23:9067–9072CrossRefPubMed

23.

Poon RT, Fan ST, Wong J (2001) Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 19:1207–1225PubMed

24.

Rydén L, Jirström K, Bendahl PO, Fernö M, Nordenskjöld B, Stål O, Thorstenson S, Jönsson PE, Landberg G (2005) Tumor-specific expression of vascular endothelial growth factor receptor 2 but not vascular endothelial growth factor or human epidermal growth factor receptor 2 is associated with impaired response to adjuvant tamoxifen in premenopausal breast cancer. J Clin Oncol 23:4695–4704CrossRefPubMed

25.

Rydén L, Stendahl M, Jonsson H, Emdin S, Bengtsson NO, Landberg G (2005) Tumor-specific VEGF-A and VEGFR2 in postmenopausal breast cancer patients with long-term follow-up. Implication of a link between VEGF pathway and tamoxifen response. Breast Cancer Res Treat 89:135–143CrossRefPubMed

26.

Guarneri V, Piacentini F, Ficarra G, Frassoldati A, D’Amico R, Giovannelli S, Maiorana A, Jovic G, Conte P (2009) A prognostic model based on nodal status and Ki-67 predicts the risk of recurrence and death in breast cancer patients with residual disease after preoperative chemotherapy. Ann Oncol 20:1193–1198CrossRefPubMed

27.

Johnston SR, Saccani-Jotti G, Smith IE, Salter J, Newby J, Coppen M, Ebbs SR, Dowsett M (1995) Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifen-resistant human breast cancer. Cancer Res 55:3331–3338PubMed

28.

Knowlden JM, Hutcheson IR, Jones HE, Madden T, Gee JM, Harper ME, Barrow D, Wakeling AE, Nicholson RI (2003) Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology 144:1032–1044CrossRefPubMed

29.

Bunone G, Briand PA, Miksicek RJ, Picard D (1996) Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J 15:2174–2183PubMed

30.

Lee H, Bai W (2002) Regulation of estrogen receptor nuclear export by ligand-induced and p38-mediated receptor phosphorylation. Mol Cell Biol 22:5835–5845CrossRefPubMed

31.

Gutierrez MC, Detre S, Johnston S, Mohsin SK, Shou J, Allred DC, Schiff R, Osborne CK, Dowsett M (2005) Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol 23:2469–2476CrossRefPubMed

32.

Svensson S, Jirström K, Rydén L, Roos G, Emdin S, Ostrowski MC, Landberg G (2005) ERK phosphorylation is linked to VEGFR2 expression and Ets-2 phosphorylation in breast cancer and is associated with tamoxifen treatment resistance and small tumours with good prognosis. Oncogene 24:4370–4379CrossRefPubMed

33.

Bergqvist J, Elmberger G, Odh J, Linderholm B, Bjohle J, Hellborg H, Nordgren H, Borg AL, Skoog L, Bergh J (2006) Activated ERK1/2 and phosphorylated oestrogen receptor alpha are associated with improved breast cancer survival in women treated with tamoxifen. Eur J Cancer 42:1104–1112CrossRefPubMed

34.

Qi X, Pohl NM, Loesch M, Hou S, Li R, Qin JZ, Cuenda A, Chen G (2007) p38alpha antagonizes p38gamma activity through c-Jun-dependent ubiquitin-proteasome pathways in regulating Ras transformation and stress response. J Biol Chem 282:31398–31408CrossRefPubMed

Title: Vascular endothelial growth factor receptor 2 and downstream p38 mitogen-activated protein kinase are possible candidate markers of intrinsic resistance to adjuvant endocrine treatment in steroid receptor positive breast cancer
Authors: Barbro K. Linderholm
Henrik Hellborg
Ulla Johansson
Lambert Skoog
Janne Lehtiö
Publication date: 01-01-2011
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2011
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-010-1252-x

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2011

Need for clarification of results in the recent meta-analysis about SULT1A1 codon 213 polymorphism and breast cancer risk

Targeting mutant p53 protein and the tumor vasculature: an effective combination therapy for advanced breast tumors

Possible risk modifications in the association between MnSOD Ala-9Val polymorphism and breast cancer risk: subgroup analysis and evidence-based sample size calculation for a future trial

A high prevalence of BRCA1 mutations among breast cancer patients from the Bahamas

Association between two polymorphisms of ABCB1 and breast cancer risk in the current studies: a meta-analysis

Safety of avoiding routine use of axillary dissection in early stage breast cancer: a systematic review

Keynote webinar | Spotlight on antibody–drug conjugates in cancer