STAT1-deficient mice spontaneously develop estrogen receptor α-positive luminal mammary carcinomas.

INTRODUCTION: Although breast cancers expressing estrogen receptor-α (ERα) and progesterone receptors (PR) are the most common form of mammary malignancy in humans, it has been difficult to develop a suitable mouse model showing similar steroid hormone responsiveness. STAT transcription factors play critical roles in mammary gland tumorigenesis, but the precise role of STAT1 remains unclear. Herein, we show that a subset of human breast cancers display reduced STAT1 expression and that mice lacking STAT1 surprisingly develop ERα+/PR+ mammary tumors. METHODS: We used a combination of approaches, including histological examination, gene targeted mice, gene expression analysis, tumor transplantaion, and immunophenotyping, to pursue this study. RESULTS: Forty-five percent (37/83) of human ERα+ and 22% (17/78) of ERα- breast cancers display undetectable or low levels of STAT1 expression in neoplastic cells. In contrast, STAT1 expression is elevated in epithelial cells of normal breast tissues adjacent to the malignant lesions, suggesting that STAT1 is selectively downregulated in the tumor cells during tumor progression. Interestingly, the expression levels of STAT1 in the tumor-infiltrating stromal cells remain elevated, indicating that single-cell resolution analysis of STAT1 level in primary breast cancer biopsies is necessary for accurate assessment. Female mice lacking functional STAT1 spontaneously develop mammary adenocarcinomas that comprise > 90% ERα+/PR+ tumor cells, and depend on estrogen for tumor engraftment and progression. Phenotypic marker analyses demonstrate that STAT1-/- mammary tumors arise from luminal epithelial cells, but not myoepithelial cells. In addition, the molecular signature of the STAT1-/- mammary tumors overlaps closely to that of human luminal breast cancers. Finally, introduction of wildtype STAT1, but not a STAT1 mutant lacking the critical Tyr701 residue, into STAT1-/- mammary tumor cells results in apoptosis, demonstrating that the tumor suppressor function of STAT1 is cell-autonomous and requires its transcriptional activity. CONCLUSIONS: Our findings demonstrate that STAT1 suppresses mammary tumor formation and its expression is frequently lost during breast cancer progression. Spontaneous mammary tumors that develop in STAT1-/- mice closely recapitulate the progression, ovarian hormone responsiveness, and molecular characteristics of human luminal breast cancer, the most common subtype of human breast neoplasms, and thus represent a valuable platform for testing novel treatments and detection modalities.

Claudin 4 identifies a wide spectrum of epithelial neoplasms and represents a very useful marker for carcinoma versus mesothelioma diagnosis in pleural and peritoneal biopsies and effusions.

We evaluated the usefulness of the tight-junction associated protein Claudin 4 (CL-4) in the diagnosis of mesothelioma and mimickers, analyzing biopsies from 454 tumors, including 82 mesotheliomas, 336 carcinomas of different origin (278 primary, 58 metastatic to serosae), 36 nonepithelial spindle cell neoplasms, as well as 97 cytological samples from reactive effusions (12), mesothelioma (23) and metastatic carcinomas (62). CL-4 was consistently negative in normal and reactive mesothelium, as well as in all 82 mesotheliomas. In contrast, strong reactivity was found in 57/58 serosal metastasis, and in 245/278 primary carcinomas, with uppermost expression (150/153) in those most frequently involved in the differential with mesothelioma (lung, breast, gastrointestinal tract, pancreas, ovary, primary serous papillary carcinoma of peritoneum). On effusions, reactive and neoplastic mesothelial cells were regularly negative, while metastatic tumor cells stained positively in 60/62 (96.8%) cases. Among spindle cell neoplasms, only 2/9 biphasic synovial sarcomas and 4/4 follicular dendritic cell sarcomas stained positively. Results indicate that CL-4 reacts with the majority of epithelial neoplasms that often metastasize to serous membranes, representing a pancarcinoma marker with extremely high sensitivity and specificity. CL-4 may be considered a primary immunohistochemical reagent to rule out the diagnosis of mesothelioma.

HER-2/neu in breast cancer: a comparative study between histology, immunohistochemistry, and molecular technique (FISH).

HER-2/neu is a protooncogene frequently overexpressed in breast cancer. Fluorescence in situ hybridization (FISH) is a technique targeting the gene amplification, while immunohisto-chemistry detects the protein expression. Usually both are applied to paraffin-embedded tissue. The authors studied HER-2 by FISH and immunohistochemistry (HercepTest) in 81 breast carcinomas. The results showed an overall concordance (correlation coefficient 0.64). In all cases with HercepTest score 0 and 1+, nonamplification of the gene was observed. Gene amplification was found in 20% of cases with a 2+ score and in 77.78% of cases with a 3+ score. Data described in literature for 3+ carcinomas showed a 3% to 10% discrepancy between protein expression and gene amplification, while in this study this difference was up to 22.22%. As a consequence, even if it is usually considered important to analyze only 2+ cases by FISH, 3+ scores nonamplified for HER-2/neu may be a new, interesting subset. Furthermore, the authors investigated the two-variables correlation between chromosome 17 copy number, protein over-expression, gene amplification, and presence of metastatic lymph nodes. Interesting results came from the correlation between the HercepTest score and the HER-2/neu gene amplification evaluation, HercepTest and chromosome 17 aneusomy, and gene amplification and lymph nodes status. In conclusion, the FISH technique can be an important and useful diagnostic tool to integrate the results of the HercepTest and to select patients for immunotherapy.

A mammary nodule mimicking breast cancer.

Metastases to the breast from extramammary tumors are rare. Several clinical, radiologic, and histologic signs can help to distinguish metastases from breast primary tumors. In the present study, we present a case of a left-sided breast metastasis from renal cancer in a 44-year-old woman whose clinical presentation was a mammary nodule in the upper internal quadrant. The patient underwent quadrantectomy with sentinel lymph node biopsy. The histology revealed a clear cell carcinoma. On computed tomography scan a 5×8-cm left renal mass with pulmonary, liver, and intrapericardial nodules was found. The patient underwent palliative care and died after 4 months. Metastasis to the breast is rare, but all of those clinical, radiologic, and histologic signs more typical of extramammary malignancies should always be considered in order to choose the best treatment strategy.

A retrospective series of long-term survivors of metastatic breast cancer in complete remission.

AIM: To describe clinical features, treatment modalities and long-term outcome of patients with overt metastatic breast cancer in complete remission for more than 5 years. PATIENTS AND METHODS: A retrospective survey of 12 patients who were referred to a single institution from 1982 to 1995. RESULTS: The majority of the long-term survivors had a good performance status, endocrine-responsive disease and a single metastatic site. Ten patients had received chemotherapy, 8 patients hormone therapy, and 2 patients had been treated with surgery followed by systemic therapies. At a median follow-up of 11.7 years, 10 of the 12 patients were still in complete remission. The median duration of complete remission was 9.2 years (range 5.0-15.7 years). CONCLUSIONS: This case series confirms that only a few metastatic breast cancer patients could potentially be cured with multidisciplinary treatments.