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Published on: May 17, 2019
Quantitative assessment of invasive mena isoforms (Menacalc) as an independent prognostic marker in breast cancer
Introduction:
Mena, 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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
High levels of Menacalc, a biomarker for invasive breast cancer cells, indicate a poor prognosis. This finding suggests Menacalc can predict metastasis risk in breast cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Mena, an Ena/VASP protein, regulates actin and is upregulated in breast cancer, promoting tumor cell invasion.
- Mena has splice variants, including Mena invasive (MenaINV) and Mena11a, differentially expressed in invasive and non-invasive tumor cells.
- A novel multiplex quantitative immunofluorescence (MQIF) approach was developed to quantify Mena variants.
Purpose of the Study:
- To develop and validate a novel biomarker, Menacalc (total Mena minus Mena11a), for assessing invasive breast cancer cells.
- To determine the association of Menacalc with patient outcomes and metastasis in breast cancer.
Main Methods:
- A multiplex quantitative immunofluorescence (MQIF) method was employed using antibodies against Mena and Mena11a.
- Menacalc was calculated for patients in two independent breast cancer cohorts (n=501 and n=296).
- Association of Menacalc with disease-specific death risk was assessed using survival analysis and multivariate analysis.
Main Results:
- Neither total Mena nor Mena11a expression correlated significantly with patient outcomes in either cohort.
- Elevated Menacalc levels were significantly associated with poor prognosis in both independent breast cancer cohorts.
- Multivariate analysis confirmed that high Menacalc is an independent predictor of poor outcome, regardless of clinical factors.
Conclusions:
- High Menacalc levels identify a breast cancer subgroup with significantly reduced disease-specific survival.
- Menacalc shows potential as a predictive biomarker for breast cancer metastasis and poor prognosis.