Quantitative assessment of invasive mena isoforms (Menacalc) as an independent prognostic marker in breast cancer

The MQIF method was applied to two independent primary breast cancer cohorts (Cohort 1 with 501 and Cohort 2 with 296 patients) using antibodies against Mena and its isoform, Mena11a. Menacalc was determined for each patient and assessed for association with risk of disease-specific death.Total Mena or Mena11a isoform expression failed to show any statistically significant association with outcome in either cohort. However, assessment of Menacalc showed that relatively high levels of this biomarker is associated with poor outcome in two independent breast cancer cohorts (log rank P = 0.0004 for Cohort 1 and 0.0321 for Cohort 2). Multivariate analysis on combined cohorts revealed that high Menacalc is associated with poor outcome, independent of age, node status, receptor status and tumor size.High Menacalc levels identify a subgroup of breast cancer patients with poor disease-specific survival, suggesting that Menacalc may serve as a biomarker for metastasis.Many genes implicated in the sequential, multi-step process of metastasis have been identified [1,2]. One of the genes identified is Mena, a member of the Ena/VASP family of proteins, which plays a key regulatory role in actin polymerization [3-6]. It has been shown to be involved in intravasation and motility of tumor cells in model systems [7,8]. In breast cancer tumors, its expression has been shown to be a key element of the tumor microenvironment for metastasis (TMEM), whose density correlates with risk of distant metastasis [9]. Importantly, Mena deficiency in the PyMT mouse breast cancer model suppresses intravasation, eliminates mortality and morbidity, and greatly reduces the frequency of metastatic dissemination to the lung [10].Mena is alternately spliced to give rise to multiple protein isoforms that are differentially expressed during tumor progression [11,12]. Two of the best characterized isoforms are MenaINV, expressed exclusively in invasive tumor cells, and Mena11a, an epithelial-specific isofo