Abstract
IntroductionMena, an Ena/VASP protein family member, is a key actin regulatory protein. Mena is up-regulated in breast cancers and promotes invasion and motility of tumor cells. Mena has multiple splice variants, including Mena invasive (MenaINV) and Mena11a, which are expressed in invasive or non-invasive tumor cells, respectively. We developed a multiplex quantitative immunofluorescence (MQIF) approach to assess the fraction of Mena lacking 11a sequence as a method to infer the presence of invasive tumor cells represented as total Mena minus Mena11a (called Menacalc) and determined its association with metastasis in breast cancer.MethodsThe 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.ResultsTotal 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.ConclusionsHigh Menacalc levels identify a subgroup of breast cancer patients with poor disease-specific survival, suggesting that Menacalc may serve as a biomarker for metastasis.
Highlights
Mena, an Ena/VASP protein family member, is a key actin regulatory protein
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
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]
Summary
Mena is up-regulated in breast cancers and promotes invasion and motility of tumor cells. Mena has multiple splice variants, including Mena invasive (MenaINV) and Mena11a, which are expressed in invasive or non-invasive tumor cells, respectively. 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 [3,4,5,6]. MenaINV, (originally termed Mena+++), expression confers a potent pro-metastatic phenotype when expressed in breast cancer cells by potentiating their chemotactic response to epidermal growth factor (EGF), thereby enhancing their ability to engage in efficient streaming motility via increasing their paracrine signaling with macrophages [3,13,14]. Mena11a expression in breast cancer cells causes formation of poorly metastatic tumors with a highly epithelial architecture that are not capable of responding to EGF chemotactic cues in vivo [14]. Mena11a expression positively correlates with, and enforces epithelial non-metastatic phenotypes, and negatively correlates with, and suppresses mesenchymal metastatic phenotypes in vitro and in vivo
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