The Mre11 complex suppresses oncogene-driven breast tumorigenesis and metastasis.

The DNA damage response (DDR) is activated by oncogenic stress, but the mechanisms by which this occurs, and the particular DDR functions that constitute barriers to tumorigenesis, remain unclear. We established a mouse model of sporadic oncogene-driven breast tumorigenesis in a series of mutant mouse strains with specific DDR deficiencies to reveal a role for the Mre11 complex in the response to oncogene activation. We demonstrate that an Mre11-mediated DDR restrains mammary hyperplasia by effecting an oncogene-induced G2 arrest. Impairment of Mre11 complex functions promotes the progression of mammary hyperplasias into invasive and metastatic breast cancers, which are often associated with secondary inactivation of the Ink4a-Arf (CDKN2a) locus. These findings provide insight into the mechanism of DDR engagement by activated oncogenes and highlight genetic interactions between the DDR and Ink4a-Arf pathways in suppression of oncogene-driven tumorigenesis and metastasis.

MR imaging features of triple-negative breast cancers.

Triple-negative (TN) breast cancers, which are associated with a more aggressive clinical course and poorer prognosis, often present with benign imaging features on mammography and ultrasound. The purpose of this study was to compare the magnetic resonance imaging features of TN breast cancers with estrogen (ER) and progesterone (PR) positive, human epidermal growth factor receptor (HER2) negative cancers. Retrospective review identified 140 patients with TN breast cancer who underwent a preoperative breast MRI between 2003 and 2008. Comparison was made to 181 patients with ER+/PR+/HER2- cancer. Breast MRIs were independently reviewed by two radiologists blinded to the pathology. Discrepancies were resolved by a third radiologist. TN cancers presented with a larger tumor size (p = 0.002), higher histologic grade (<0.001), and were more likely to be unifocal (p = 0.018) compared with ER+/PR+/HER2- tumors. MRI features associated with TN tumors included mass enhancement (p = 0.026), areas of intratumoral high T2 signal intensity (p < 0.001), lobulated shape (p < 0.001), rim enhancement (p < 0.001), and smooth margins (p = 0.005). Among the TN tumors with marked necrosis, 26% showed a large central acellular zone of necrosis.

Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma.

How organ-specific metastatic traits arise in primary tumors remains unknown. Here, we show a role of the breast tumor stroma in selecting cancer cells that are primed for metastasis in bone. Cancer-associated fibroblasts (CAFs) in triple-negative (TN) breast tumors skew heterogeneous cancer cell populations toward a predominance of clones that thrive on the CAF-derived factors CXCL12 and IGF1. Limiting concentrations of these factors select for cancer cells with high Src activity, a known clinical predictor of bone relapse and an enhancer of PI3K-Akt pathway activation by CXCL12 and IGF1. Carcinoma clones selected in this manner are primed for metastasis in the CXCL12-rich microenvironment of the bone marrow. The evidence suggests that stromal signals resembling those of a distant organ select for cancer cells that are primed for metastasis in that organ, thus illuminating the evolution of metastatic traits in a primary tumor and its distant metastases.

Black race as a prognostic factor in triple-negative breast cancer patients treated with breast-conserving therapy: a large, single-institution retrospective analysis.

Triple-negative breast cancer (TNBC) disproportionately affects black women. However, black race as a prognostic factor in TNBC has not been well studied. We evaluated the effect of race, among other variables, on outcomes in women with TNBC. A total of 704 patients with stages I-III TNBC treated with breast-conserving surgery ± adjuvant radiation therapy (RT) and chemotherapy were identified from an institutional database. Competing risk analyses, Kaplan-Meier methods, and Cox proportional hazards models identified associations among clinicopathologic variables on locoregional recurrence (LRR), distant recurrence (DR), and overall survival (OS). LRR was defined as a biopsy proven, triple receptor-negative recurrence in the ipsilateral breast or regional lymph nodes. At a median follow-up of 51 months, there were 55 LRR, 61 DR, and 111 death events. Compared to non-black women, black women had higher disease stage and were more likely to receive axillary lymph node dissection, chemotherapy, and nodal irradiation (all P < 0.05). After adjustment for stage, age, lymphovascular invasion, chemotherapy, and RT on multivariate analysis, black race was prognostic for increased risk of LRR (hazard ratio [HR] = 3.17; 95 % confidence interval: 1.7-5.8; P = 0.0002). The 5-year risk of regional recurrence was higher in black women (10 vs. 2 %, P < 0.0001), but local failures were similar between groups (3.0 vs. 5.3 %, P = 0.15). RT was an independent predictor for decreased LRR and increased OS on multivariate analyses (P = 0.0006 and P = 0.0003, respectively). Black women with TNBC had equivalent local control, but higher risk of regional nodal failure, compared with non-black counterparts. The routine use of comprehensive nodal irradiation may be beneficial for black women with TNBC.

DNA mismatch repair deficiency in breast carcinoma: a pilot study of triple-negative and non-triple-negative tumors.

Recent studies have suggested that breast cancer is part of the tumor spectrum in Lynch syndrome (LS). However, the frequency and significance of DNA mismatch repair (MMR) deficiency in breast carcinoma in general is unclear. Some triple-negative breast carcinomas (TNBCs) have morphologic features similar to those described in LS-associated colorectal carcinomas; therefore, we hypothesized that TNBCs might be more likely to have MMR deficiency. In this study, we tested our hypothesis in a series of 226 TNBCs along with a control series of 90 non-triple-negative tumors, utilizing DNA MMR protein immunohistochemistry followed by PCR microsatellite instability testing and MLH1 promoter methylation testing. By immunohistochemistry, we identified 4 triple-negative carcinomas (4/226, 1.8%) showing loss of MMR proteins (3 lost MLH1 and PMS2, and 1 lost MSH2 and MSH6); whereas none of the 90 non-triple-negative carcinomas showed loss of protein. Further testing of the 3 MLH1/PMS2 protein-deficient carcinomas identified 1 tumor showing high-frequency microsatellite instability and MLH1 promoter hypermethylation. All 4 MMR protein-deficient carcinomas were ductal type with high histologic and nuclear grades. Prominent lymphocytic infiltration was noted in 2 tumors. The clinical characteristics and survival outcome varied widely among the 4 patients. In conclusion, our results suggest that DNA MMR deficiency is rare in breast carcinoma, and as such, testing of breast carcinoma for the detection of LS may best be restricted to high-risk individuals only. Our data also suggest that not all MMR protein-deficient breast tumors show microsatellite instability, and MLH1 promoter methylation is the molecular basis for at least a subset of microsatellite instable breast tumors. Although MMR-deficient breast carcinomas share certain morphologic features with the more typical types of LS-associated tumors, better characterization, and a better understanding of their clinical behavior await further analysis with a larger sample size.

Synchronous breast cancers with different morphologic and molecular phenotypes occurring in Lynch syndrome: what does the heterogeneity imply?

The increasingly widespread use of immunohistochemistry in the detection of DNA mismatch repair proteins has led to the observation of various unusual tumor types that occur in Lynch syndrome and exhibit mismatch repair protein deficiency. Understanding the clinical significance of such unusual tumors has become increasingly desirable. Here, we report a case of 2 synchronous breast cancers occurring in a 74-year-old woman who carried a deleterious germline mutation in MSH2 and who survived an endometrial and a colonic carcinoma. Both breast cancers were of lobular type with similar expression patterns for estrogen receptor, progesterone receptor, and Her2/neu. However, the 2 cancers differed in other characteristics. One tumor showed a solid alveolar histologic pattern with prominent tumor-infiltrating lymphocytes and loss of MSH2 and MSH6 protein on immunohistochemical staining. In contrast, the other tumor was of classic type with no apparent lymphocytic infiltration and no loss of mismatch repair protein. Such a case carries practical implications as it suggests that certain breast cancers may serve as tissue samples for the detection of mismatch repair deficiency in families at high risk for Lynch syndrome, thus expanding the test sample repertoire for genetic workup in these families. Furthermore, the case exemplifies the complexity of tumorigenesis in Lynch syndrome patients. The observation that, of the 2 breast cancers, increased tumor-infiltrating lymphocytes were present only in the tumor that showed mismatch repair protein abnormality is in keeping with what has been observed in the colon and other sites. Such persistent genotype-phenotype correlation across different organs affords the promise that molecular classification may allow identification of biologically distinct tumor subsets beyond the confines of the tumor's primary anatomic location.

Fascin expression in serous tumors of ovary correlates with aggressiveness of malignancy.

Ovarian serous tumors make up about one-fourth of all ovarian tumors. There is a spectrum of proliferation and cellular atypia in these tumors with benign serous cystadenoma, borderline tumors, and low grade or type I serous carcinoma at the lower end and type II or high-grade serous papillary cystadenocarcinoma at the higher end. Fascin is a globular actin cross-linking protein involved in cell motility that has been shown to be upregulated in many human neoplasms and associated with the aggressiveness of malignancy. The aim of this study was to investigate fascin expression in serous tumors of ovary and to evaluate its relationship with the aggressiveness of tumor. Sections from a total of 66 serous tumors of ovary were collected including 26 serous carcinomas, 20 borderline serous tumors, and 20 benign serous cystadenomas. Ten benign ovaries with inclusion cysts were used as controls. Sections were immunostained with fascin. Fascin expression was significantly increased in borderline (13/20, 65%) and malignant serous tumors (22/26, 84%) compared with benign serous cystadenoma (0/20) (P<0.001). There was increased quantitative expression of fascin in carcinoma compared with borderline tumors (diffuse versus patchy). Fascin expression also correlated well with the tumor grade in serous carcinoma cases with 8/12 (66%) of grade I/II tumors staining positive compared with all 14 (100%) of grade III tumors showing fascin expression (P<0.05). Our findings suggest that upregulation of fascin plays a role in increasing aggressiveness of serous ovarian tumors and could potentially be a molecular therapeutic target and a prognostic marker.