The prognostic value of MARCKS-like 1 in lymph node-negative breast cancer

Department of Pathology, Stavanger University Hospital, PO Box 8100, 4068 Stavanger, Norway.
Breast Cancer Research and Treatment (Impact Factor: 3.94). 07/2012; 135(2):381-90. DOI: 10.1007/s10549-012-2155-9
Source: PubMed


There is a need for new biomarkers to more correctly identify node-negative breast cancer patients with a good or bad prognosis. Myristoylated alanine-rich C kinase substrate like-1 (MARCKSL1) is a membrane-bound protein that is associated with cell spreading, integrin activation and exocytosis. Three hundred and five operable T(1,2)N(0)M(0) lymph node-negative breast cancer patients (median follow-up time 121 months, range 10-178 months) were evaluated for MARCKSL1 expression by immunohistochemistry and quantitative real-time PCR. The results were compared with classical prognosticators (age, tumor diameter, grade, estrogen receptor, and proliferation), using single (Kaplan-Meier) and multivariate survival analysis (Cox model). Forty-seven patients (15 %) developed distant metastases. With single and multivariate analysis of all features, MARCKSL1 protein expression was the strongest prognosticator (P < 0.001, HR = 5.1, 95 % CI = 2.7-9.8). Patients with high MARCKSL1 expression (n = 23) showed a 44 % survival versus 88 % in patients with low expression at 15-year follow-up. mRNA expression of MARCKSL1 in formalin fixed paraffin-embedded tissue was also prognostic (P = 0.002, HR = 3.6, 95 % CI = 1.5-8.3). However, the prognostic effect of high and low was opposite from the protein expression, i.e., low expression (relative expression ≤ 0.0264, n = 76) showed a 79 % survival versus 92 % in those with high expression of MARCKSL1 mRNA. Multivariate analysis of all features with distant metastases free survival as the end-point showed that the combination of MARCKSL1 protein and phosphohistone H3 (PPH3) has the strongest independent prognostic value. Patients with high expression (≥13) of PPH3 and high MARCKSL1 protein had 45 % survival versus 78 % survival for patients with low MARCKSL1 protein expression and high expression (≥13) of PPH3. In conclusion, MARCKSL1 has strong prognostic value in lymph node-negative breast cancer patients, especially in those with high proliferation.

31 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cell migration is a fundamental biological function, critical during development and regeneration, whereas deregulated migration underlies neurological birth defects and cancer metastasis. MARCKS-like protein 1 (MARCKSL1) is widely expressed in nervous tissue, where, like Jun N-terminal protein kinase (JNK), it is required for neural tube formation, though the mechanism is unknown. Here we show that MARCKSL1 is directly phosphorylated by JNK on C-terminal residues (S120, T148, and T183). This phosphorylation enables MARCKSL1 to bundle and stabilize F-actin, increase filopodium numbers and dynamics, and retard migration in neurons. Conversely, when MARCKSL1 phosphorylation is inhibited, actin mobility increases and filopodium formation is compromised whereas lamellipodium formation is enhanced, as is cell migration. We find that MARCKSL1 mRNA is upregulated in a broad range of cancer types and that MARCKSL1 protein is strongly induced in primary prostate carcinomas. Gene knockdown in prostate cancer cells or in neurons reveals a critical role for MARCKSL1 in migration that is dependent on the phosphorylation state; phosphomimetic MARCKSL1 (MARCKSL1S120D,T148D,T183D) inhibits whereas dephospho-MARCKSL1S120A,T148A,T183A induces migration. In summary, these data show that JNK phosphorylation of MARCKSL1 regulates actin homeostasis, filopodium and lamellipodium formation, and neuronal migration under physiological conditions and that, when ectopically expressed in prostate cancer cells, MARCKSL1 again determines cell movement.
    Molecular and Cellular Biology 07/2012; 32(17):3513-26. DOI:10.1128/MCB.00713-12 · 4.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Our purpose was to investigate whether Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) expression could be linked to prognosis in invasive breast carcinomas. NHERF1, an ezrin-radixin-moesin (ERM) binding phosphoprotein 50, is involved in the linkage of integral membrane proteins to the cytoskeleton. It is therefore believed to have an important role in cell signaling associated with changes in cell cytoarchitecture. NHERF1 expression is observed in various types of cancer and is related to tumor aggressiveness. To date the most extensive analyses of the influence of NHERF1 in cancer development have been performed on breast cancer. However, the underlying mechanism and its prognostic significance are still undefined. NHERF1 expression was studied by immunohistochemistry (IHC) in a cohort of 222 breast carcinoma patients. Association of cytoplasmic and nuclear NHERF1 expression with survival was analyzed. Disease-free survival (DFS) and overall survival (OS) were determined based on the Kaplan-Meier method. Cytoplasmic NHERF1 expression was associated with negative progesterone receptor (PgR) (P=0.017) and positive HER2 expression (P=0.023). NHERF1 also showed a nuclear localization and this correlated with small tumor size (P=0.026) and positive estrogen receptor (ER) expression (P=0.010). Multivariate analysis identified large tumor size (P=0.011) and nuclear NHERF1 expression (P=0.049) to be independent prognostic variables for DFS. Moreover, the nuclear NHERF1(-)/ER(-) immunophenotype (27%) was statistically associated with large tumor size (P=0.0276), high histological grade (P=0.0411), PgR-negative tumors (P<0.0001) and high proliferative activity (P=0.0027). These patients had worse DFS compared with patients with nuclear NHERF1(+)/ER(+) tumors (75.4% versus 92.6%; P=0.010). These results show that the loss of nuclear NHERF1 expression is associated with reduced survival, and the link between nuclear NHERF1 and ER expression may serve as a prognostic marker for the routine clinical management of breast cancer patients.
    Cell Death & Disease 11/2013; 4(11):e904. DOI:10.1038/cddis.2013.439 · 5.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Development of signature biomarkers has gained considerable attention in the last decade. Although, the most well-known examples of biomarker panels stem from gene expression studies, proteomic panels are becoming more relevant, with the advent of targeted mass spectrometry-based methodologies. At the same time, the development of multigene prognostic classifiers for early stage breast cancer patients has resulted in a wealth of publicly available gene expression data from thousands of breast cancer specimens. In the present study, we integrated transcriptome and proteome-based platforms to identify genes and proteins related to patient survival. Candidate biomarker proteins have been identified in a previously generated breast cancer tissue extract proteome. A mass spectrometry-based assay was then developed for the simultaneous quantification of these twenty proteins in breast cancer tissue extracts. We quantified the relative expression levels of the twenty potential biomarkers in a cohort of 96 tissue samples from patients with early stage breast cancer. We identified two proteins, KPNA2 and CDK1, which showed potential to discriminate between estrogen receptor positive patients of high and low risk of disease recurrence. The role of these proteins in breast cancer prognosis warrants further investigation.
    Journal of Proteome Research 05/2014; 13(6). DOI:10.1021/pr500352e · 4.25 Impact Factor
Show more

Similar Publications