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

• Published in: Breast cancer research and treatment 2011-01, Vol.125 (2), p.457-465
• Main Authors: Linderholm, Barbro K, Hellborg, Henrik, Johansson, Ulla, Skoog, Lambert, Lehtiö, Janne
• Format: Article
• Language: English
• Subjects: Adjuvant treatment; Antineoplastic Agents, Hormonal - therapeutic use; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cancer; Cancer and Oncology; Cancer och onkologi; Cancer research; Cancer therapies; Chemotherapy, Adjuvant; Clinical Trial; Clinical trials; Diagnosis; Drug resistance; Drug Resistance, Neoplasm; Endocrine therapy; Enzyme-Linked Immunosorbent Assay; Enzymes; Female; Gynecology. Andrology. Obstetrics; Humans; Intrinsic and required resistance; Kinases; Mammary gland diseases; Medical sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Mitogens; Neoplasm Recurrence, Local; Oncology; p38 Mitogen-Activated Protein Kinases - metabolism; p38MAPK; Prognosis; Protein kinases; Receptors, Estrogen - metabolism; Receptors, Progesterone - metabolism; Signal Transduction; Survival Rate; Tamoxifen; Tamoxifen - therapeutic use; Treatment Outcome; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGFR2
• ISSN: 0167-6806; 1573-7217; 1573-7217
• DOI: 10.1007/s10549-010-1252-x

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.