Low Mre11 Complex Expression Identifies a Subset of Triple Negative Breast Cancer With Excellent Outcomes

Abstract

The Mre11 complex is an initiator of the DNA damage response, and has been implicated as a tumor suppressor in breast cancer. Disruption of the Mre11 complex results in marked hypersensitivity to DNA damaging agents. We investigated whether expression of this ubiquitous nuclear protein complex is disrupted in triple negative (ER-/PR-/HER2-) breast cancer (TNBC), and whether there is any association with clinical outcomes. Tissue microarrays were constructed from 271 patients with non-metastatic TNBC (ER/PR < 1%; HER2 0/1+, or HER2 2+/FISH not amplified) who underwent surgical resection of their primary tumor at our institution between 2002 and 2007. Exclusion criteria were < 1 cm primary tumor size, prior breast radiation, inflammatory breast cancer, and neoadjuvant chemotherapy. Immunohistochemistry (IHC) was performed using rabbit polyclonal anti-sera generated against human Mre11 (1:3000) and human Nbs1 (1:3000). Tumors were classified as low-expressors of the Mre11 complex if < 10% of cancer cells had detectable nuclear protein expression of Mre11 and/or Nbs1 relative to background staining levels. Lack of immunoreactivity was confirmed by repeating the IHC using whole tissue sections in a subset of Mre11 complex low-expressors. Fisher’s exact test was used for correlation with clinicopathological features, and log-rank and Cox proportional hazards were used for survival analyses. Two hundred fifty-six of the 271 TNBCs were evaluable for Mre11 and/or Nbs1 expression by IHC. Twenty-three (9.0%) of these tumors were Mre11 complex low-expressors. Mre11 complex expression did not correlate with any significant differences in clinicopathological features (age, menopausal status, tumor size, grade, LVI, or nodal involvement). Median follow-up for the cohort was 52 months: 84% of the patients received adjuvant chemotherapy and 61% radiation therapy. Low Mre11 complex expression was associated with improved overall survival (5 year OS 100% vs 77%, P = 0.013), with a hazard ratio of 0.32 (95% CI = 0.13 to 0.79). Similar trends were also observed for locoregional recurrence and distant metastasis-free survival. A multivariate model for low Mre11 expression, tumor size, and lymph node involvement demonstrates a trend towards favorable prognostic association of low Mre11 expression with overall survival (HR = 0.18; p = 0.09). A subset of TNBC expresses significantly reduced levels of the Mre11 complex by IHC, and is associated with improved overall survival in a cohort of patients frequently treated with adjuvant therapy. Given the known functions of Mre11 in the DNA damage response, we propose that low Mre11 complex expression may define a subset of TNBC that is hypersensitive to DNA damaging therapy and is associated with excellent patient outcomes.