IntroductionAlthough 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.MethodsWe used a combination of approaches, including histological examination, gene targeted mice, gene expression analysis, tumor transplantaion, and immunophenotyping, to pursue this study.ResultsForty-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.ConclusionsOur 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.

The use of neoadjuvant systemic therapy in the treatment of breast cancer patients is increasing beyond the scope of locally advanced disease. Imaging provides important information in assessing response to therapy as a complement to conventional tumor measurements via physical examination. The purpose of this article is to discuss the advantages and limitations of current assessment methods, as well as review functional and molecular imaging approaches being investigated as emerging techniques for evaluating neoadjuvant therapy response for patients with primary breast cancer. RSNA, 2017.

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Benign breast disease (BBD) is a broad category of diagnoses reported to convey a variable degree of increased risk of developing breast cancer. A meta-analysis of the existing literature was performed to quantify the risk estimate associated with BBD. Pubmed, Google Scholar, and EMBASE databases were searched in January 2011. English retrospective and prospective observational studies published from 1972 to 2010 evaluating BBD and the risk of breast cancer were included with data acquisition reported from 1930 to 2007. Eligibility was performed independently following a standardized protocol for full-text publication review by a single reviewer and reviewed by a second author. Of the 3,409 articles retrieved from the literature search, 32 studies met the selection criteria. Reported risk estimates, including relative risk, odds ratio, standardized incidence ratios, rate ratio, hazards ratio, and incidence rate ratio, were the primary outcomes extracted. The most commonly reported pathologies were decided prior to extraction and organized into the following categories for analysis of the extracted risk estimate: non-proliferative disease (NPD), proliferative disease without atypia, benign breast disease not otherwise specified (BBD), and atypical hyperplasia not otherwise specified (AHNOS). The mean age at benign breast biopsy was 46.1 years and the mean age of developing breast cancer was 55.9 years. The mean follow-up length was 12.8 years (range 3.3-20.6). The summary risk estimate of developing breast cancer for NPD was 1.17 (N = 8; 95% CI 0.94-1.47). Proliferative disease without atypia was associated with significantly increased risk of future breast cancer, summary relative risk 1.76 (N = 15; 95% CI 1.58-1.95). The summary risk estimate for AHNOS was 3.93 (N = 13; 95% CI 3.24-4.76). This meta-analysis demonstrates that proliferative benign breast disease with or without atypia is associated with a significant increase in risk of developing breast cancer. These data support management strategies for women with benign breast disease such as additional screening methods or chemoprevention.