The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer

More than 60% of all breast neoplasias are ductal carcinomas expressing estrogen (ER) and progesterone receptors (PR). In contrast, most of the spontaneous, chemically or MMTV induced tumors, as well as tumors arising in genetically modified mice do not express hormone receptors. We developed a model of breast cancer in which the administration of medroxyprogesterone acetate (MPA) to BALB/c female mice induces mammary ductal carcinomas with a mean latency of 52 weeks and an incidence of about 80%. These tumors are hormone-dependent, metastatic, express both ER and PR, and are maintained by syngeneic transplants. The model has been further refined to include mammary carcinomas that evolve through different stages of hormone dependency, as well as several hormone-responsive cell lines. In this review, we describe the main features of this tumor model, highlighting the role of PR as a trigger of key signaling pathways mediating tumor growth. In addition, we discussthe relevance of this model in comparison with other currently used breast cancer models pointing out its advantages and limitations and how, this model may be suitable to unravel key questions in breast cancer.Fil: Lanari, Claudia Lee Malvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Lamb, Caroline Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Fabris, Victoria Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Helguero, Luisa A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Soldati, Rocío. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Bottino, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Giulianelli, Sebastian Jesus. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Cerliani, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Wargon, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Molinolo, Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Public Health Service. National Institute Of Health; Estados Unido

THE MENACE IN BREAST PATHOLOGY

Diagnosis by non-operative procedures has of late become the standard of care. This helps the pathologist to make far reaching decisions on small tissue samples. Haematoxylin and eosin (H&E)-stained sections estimation with analytical thinking assisted by the significant use of immunohistochemistry (IHC) and other tests, resume to be the bulwark of histological diagnosis. This review aims to accentuate the hidden difficulty in the interpretation of breast lesions that could diversely guide to under diagnosis, over diagnosis, or incorrect categorization of malignancy, with possible dire after effects to the patients. The review focusses on interpretation of H&E and IHC in breast pathology and aims to complement existing literature on the subject. 1,2,3,4Entities that may result in over diagnosis of malignancy

Metaplastic carcinomas of the breast without evidence of epithelial differentiation: a diagnostic approach for management

AIMS: Although rare, malignant sarcomatoid breast tumours without evidence of epithelial differentiation comprise a diagnostic challenge with management implications. Earlier studies have generally considered these to be primary breast sarcomas; however, supporting evidence is lacking and management remains variable. This study aimed to provide an evidence-based approach to improve consistency of diagnosis and management for such cases. METHODS AND RESULTS: A large series (n=140) of metaplastic breast carcinoma (MBC) diagnosed in Nottingham over 18 years was analysed. Only cases with available data on immunohistochemical expression of cytokeratins (CKs) were included. The prevalence and pattern of expression for various CKs were assessed and details of tumours negative for CKs were collected. A diagnostic approach based on our experience is provided. 47 cases (34%) showed foci of conventional type invasive breast carcinoma or DCIS, whereas 93 cases (66%) were diagnosed as MBC based on morphology and/or CK expression. 97 cases (69%) were negative for one or more CKs, with 18 cases (13%) negative for 5 or more CKs. 8 cases (6%) lacked expression of all CKs tested. Further examination showed evidence of carcinomatous nature in 5 cases, whereas 3 were diagnosed as MBC following extensive diagnostic workup and on our experience. CONCLUSION: This study suggests that MBC represent a spectrum of neoplasms with some lacking CKs expression. Sarcomatoid neoplasms of the breast lacking evidence carcinomatous morphology and CK expression may represent an extreme end of differentiation that can be considered as carcinomas rather than sarcomas for management purposes (following extensive workup)

Pathological Diagnosis, Work-Up and Reporting of Breast Cancer 1st Central-Eastern European Professional Consensus Statement on Breast Cancer

Abstract This text is based on the recommendations accepted by the 4th Hungarian Consensus Conference on Breast Cancer, modified on the basis of the international consultation and conference within the frames of the Central-Eastern European Academy of Oncology. The recommendations cover non-operative, intraoperative and postoperative diagnostics, determination of prognostic and predictive markers and the content of cytology and histology reports. Furthermore, they address some specific issues such as the current status of multigene molecular markers, the role of pathologists in clinical trials and prerequisites for their involvement, and some remarks about the future.The 1st Central-Eastern European Professional Consensus Statements on Breast Cancer were initiated, organized and granted by the Central-Eastern European Academy of Oncology (CEEAO), the National Institute of Oncology, Hungary and the Bács-Kiskun County Teaching Hospital. This regional oncological project was supported by Prof. Miklós Kásler, founder of CEEAO, Minister of Human Capacities, the Government of Hungary

Triple-negative breast cancer histological subtypes with a favourable prognosis

Triple-negative breast cancers (TNBC), as a group of tumours, have a worse prognosis than stage-matched non-TNBC and lack the benefits of routinely available targeted therapy. However, TNBC is a heterogeneous group of neoplasms, which includes some special type carcinomas with a relatively indolent course. This review on behalf of the European Working Group for Breast Screening Pathology reviews the literature on the special histological types of BC that are reported to have a triple negative phenotype and indolent behaviour. These include adenoid cystic carcinoma of classical type, low-grade adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma, low-grade mucoepidermoid carcinoma, secretory carcinoma, acinic cell carcinoma, and tall cell carcinoma with reversed polarity. The pathological and known molecular features as well as clinical data including treatment and prognosis of these special TNBC subtypes are summarised and it is concluded that many patients with these rare TNBC pure subtypes are unlikely to benefit from systemic chemotherapy. A consensus statement of the working group relating to the multidisciplinary approach and treatment of these rare tumour types concludes the review

TRIM24 as an Oncogene in the Mammary Gland

Despite the many advances made in breast cancer research and treatments, breast cancer remains one of the deadliest diseases plaguing women worldwide. While many findings on genetic mutations and their role in predisposing people to breast cancer have been uncovered, we are just beginning to understand the extent to which epigenetic regulators promote tumorigenic phenotypes, metastasis, and chemotherapeutic resistance. Moreover, new experimental tools offer the ability to address questions we were previously unable to assess. My project takes advantage of a new mouse model to understand the role of a proto-oncogenic, transcriptional co-regulator, TRIM24, in mammary gland development and disease. We previously reported an unknown binding partner and negative regulator of p53, Tripartite Motif protein 24 (TRIM24). TRIM24 is a multifunctional protein, which acts as a co-regulator of estrogen receptor, a histone reader with tandem PHD and Bromo domains, and a ubiquitin E3-ligase targeting p53 by its RING domain. TRIM24 is over-expressed in human breast cancers, which is correlated with poor patient survival. Previous in cellulo studies in our lab show that TRIM24 over-expression leads to transformation of immortalized human mammary epithelial cells. However, whether over-expression of TRIM24 drives cancer development in vivo remains unknown. To address this gap in our knowledge, we developed a physiologically relevant mouse model to determine if over-expression of TRIM24 promotes tumor development in mammary epithelial cells, consistent with TRIM24 function as an oncogene. We hypothesize that TRIM24 acts as an oncogene in the mammary gland. To test this hypothesis, we generated transgenic mice, which in the presence of cre-recombinase, conditionally over-express mouse TRIM24 fused to a C-terminal FLAG epitope tag. Our studies reveal that increased expression of Trim24 in the mouse mammary gland is sufficient to drive tumorigenesis by 8 months of age. To facilitate genome wide and targeted therapeutic studies, I developed multiple primary cell lines (tumor and normal mammary epithelia) from each genotype. Colony formation and proliferation assays indicate that over-expression of TRIM24 gives cells a survival and proliferative advantage. RNA-deep sequencing and genome-wide binding profiles of these tumor-derived cell lines reveal that TRIM24 over-expression may be a direct driver of the epithelial-mesenchymal transition (EMT). These data corroborate unpublished in cellulo data from our lab, which implicate TRIM24 as a metastasis-promoting protein through its ability to activate EMT gene expression. Furthermore, we have observed an over-representation of metaplastic breast carcinomas (MpBC), a rare and devastatingly aggressive disease that has an EMT signature, in profiles of tumors generated in our mouse model. We have performed exome-sequencing, RNA-sequencing and immunohistochemistry on mice, which are currently being compared to human MpBC patient samples with the end goal of identifying the common alterations and substantiate TRIM24 as a player in the development of the MpBC phenotype. Finally, we present our mouse model as a useful tool to test the efficacy of potential therapeutics targeting MpBC and other breast cancers