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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

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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.

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Acknowledgments

This study was supported by grants from the Swedish Research Council (K2008-54X-20639-01-3), the Swedish State under the LUA-agreement (Sahlgrenska University Hospital, Gothenburg) (VGFOUREG-75911), the King Gustav V Jubilee Clinic Cancer Research Foundation, Gothenburg (2009:49), and the Gösta Milton Foundation, Stockholm, Sweden.

Conflict of interest

None of the authors have any conflict of interest that can be perceived as prejudicing the impartiality of the research reported.

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Authors and Affiliations

  1. Department of Oncology, Sahlgrenska University Hospital, 41345, Gothenburg, Sweden

    Barbro K. Linderholm

  2. Karolinska Biomic Centre (KBC), Karolinska University Hospital, Stockholm, Sweden

    Barbro K. Linderholm & Janne Lehtiö

  3. Regional Oncologic Centre, Karolinska University Hospital, Stockholm, Sweden

    Henrik Hellborg & Ulla Johansson

  4. Department of Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden

    Lambert Skoog

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  1. Barbro K. Linderholm
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  2. Henrik Hellborg
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Correspondence to Barbro K. Linderholm.

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Linderholm, B.K., Hellborg, H., Johansson, U. et al. 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. Breast Cancer Res Treat 125, 457–465 (2011). https://doi.org/10.1007/s10549-010-1252-x

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  • DOI: https://doi.org/10.1007/s10549-010-1252-x

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