This study aimed to determine the role of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an N6 -methyladinosine reader, in the progression and distant metastasis of breast cancer.

IGF2BP3 expression was assessed in 152 pairs of breast cancer and adjacent normal tissue (ANT) by real-time quantitative polymerase chain reaction and in 561 cases of breast cancer and 163 cases of ANT by immunohistochemistry. Survival curves were estimated using the Kaplan-Meier method and then compared statistically using the log-rank test. The prognostic role of IGF2BP3 was determined by Cox regression analysis.

Analysis of public gene data sets revealed that IGF2PB3 predicted distant metastasis in breast cancer and was highly correlated with brain metastasis. In the clinical retrospective cohort, the positive rate of IGF2BP3 increased gradually with breast cancer progression. Positive IGF2BP3 expression was related to poor distant metastasis-free survival (DMFS, p = .030) and Cox regression analysis identified IGF2BP3 as an independent risk factor for DMFS (hazard ratio, 1.876; 95% confidence interval, 1.128-3.159; p = .019). Positive IGF2BP3 expression was markedly related to breast cancer brain metastasis (p = .011) but not to lung and bone metastasis. Moreover, patients with IGF2BP3-positive brain metastasis had lower survival than patients with IGF2BP3-negative brain metastasis (p = .041). Gene expression profiling results indicated that high IGF2BP3 expression was associated with the PD-1 checkpoint pathway, HER2-HER3 signaling, and epithelial-mesenchymal transition.

IGF2BP3 may serve as a novel predictive biomarker and a potential therapeutic target for breast cancer brain metastasis, which warrants further investigation.

As an m6 A reader, IGF2BP3 is dysregulated and implicated in various cancers but its role in breast cancer has not been fully clarified. In this study, we found that IGF2BP3 was upregulated in breast cancer and IGF2BP3 expression increased gradually during breast cancer progression. IGF2BP3 expression exerted no effect on the overall survival and breast cancer-specific survival of breast cancer patients; however, IGF2BP3-positive patients were more likely to develop distant metastasis than IGF2BP3-negative patients. In addition, IGF2BP3 was associated with brain-specific metastasis in breast cancer patients. These findings warrant further investigation because they provide a rationale for novel predictive or therapeutic approaches.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and T cell/histiocyte-rich large B-cell lymphoma (THRLBCL) have overlapping histological features that make their diagnosis challenging. Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is a recently proposed diagnostic marker for Hodgkin's lymphoma. The aim of this study was to determine the ability of IMP3 in differentiating NLPHL from THRLBCL.

In this retrospective study, the formalin-fixed paraffin-embedded blocks from 56 patients (28 NLPHL and 28 large B cell lymphoma (LBCL, including 16 THRLBCL and 12 DLBCL, NOS) cases based on immunohistochemistry (IHC) were included. Sample sections were stained for IMP3 using IHC method. Moderate to strong staining in at least 10% of tumor cells was considered positive IMP3 expression.

The mean age of the patients was 41.25 ± 16.08 years old. The majority of the patients were male. There was a significant age difference between NLPHL (34.61 ± 16.44 years old) and LBCL (47.89 ± 12.85 years) groups (p = 0.001). No significant difference was seen in gender and site between NLPHL and LBCL groups. The expression of IMP3 was mainly strong in LBCL group, while it was heterogeneously distributed among NLPHL samples ranging from weak to strong (p < 0.001). It was determined that strong IMP3 expression at 55.00% can differentiate LBCL from NLPHL with 71.4% sensitivity and 71.4% specificity.

Our findings showed that IMP3 may be a good complement in differentiating NLPHL cases from THRLBCL.

Metastasis is the leading cause of breast cancer (BC)-related deaths. Circular RNAs (circRNAs) have emerged as essential regulators for cancer progression and metastasis. Therefore, the objective of this study was to investigate the role of circRNAs in BC metastasis and related mechanism. In this study, we established the BC cell line with high or low potential of metastasis. RNA sequencing, migration and invasion assay, Fluorescence in situ hybridization, luciferase report assay, circRNA pulldown, and transmission electron microscopy were performed to elucidate the molecular mechanism. The results showed that circRNA circFOXK2 was significantly increased in BC cells with high metastatic ability, and the upregulation of circFOXK2 was correlated with poor clinicopathological characteristics. Functional experiments demonstrated that overexpression of circFOXK2 promoted migration and invasion of BC cells. Also. circFOXK2 could act with IGF2BP3, an RNA-binding protein, and miR-370 to synergistically promote BC metastasis. Moreover, miR-370 could be transferred through exosomes to enhance the metastatic ability of recipient cells. In conclusion, circFOXK2 functions as a key regulator in BC metastasis, and the role of circFOXK2 on BC metastasis is tightly associated with the involvement of IGF2BP3 and miR-370. CircFOXK2 might serve as a potential biomarker for the diagnosis and treatment of BC.

The insulin-like growth factor-2 mRNA-binding proteins (IGF2BPs) pertain to a highly conservative RNA-binding family that works as a post-transcriptional fine-tuner for target transcripts. Emerging evidence suggests that IGF2BPs regulate RNA processing and metabolism, including stability, translation, and localization, and are involved in various cellular functions and pathophysiologies. In this review, we summarize the roles and molecular mechanisms of IGF2BPs in cancer development and progression. We mainly discuss the functional relevance of IGF2BPs in embryo development, neurogenesis, metabolism, RNA processing, and tumorigenesis. Understanding IGF2BPs role in tumor progression will provide new insight into cancer pathophysiology.

Adenoid cystic carcinoma (ACC) is most commonly seen in the salivary glands but may occur at other sites. Primary or metastatic involvement of the skin is unusual. We report 2 cases of ACC with unusual presentation. In the first case, a 55-year-old woman presented with a cutaneous lesion on the right shin, and final pathology showed ACC. An extracutaneous origin was excluded by clinical and imaging studies. In the second case, a 49-year-old woman presented with a nodule on the breast, and biopsy confirmed high-grade ACC (>30% solid areas). She underwent lumpectomy and subsequent mastectomy after recurrence. Sixteen months after the initial diagnosis of ACC of the breast, distant metastases at multiple sites, including the skin, were identified. This report will increase awareness of these rare presentations of cutaneous ACC and allow correct diagnosis and appropriate management of such cases.

The cross-talk between RNA binding proteins (RBPs) and microRNAs (miRNAs) in the regulation of gene expression is a complex process. Here, we describe a new mode of regulation of TRIM25 expression mediated by an antagonistic interplay between IGF2BP3 and miR-3614-3p.

The expression level of TRIM25, IGF2BP3, pri-miR-3614 and miR-3614-3p in breast cancer (BC) tissues, non-tumor tissues and BC cell lines were detected by qRT-PCR, Western blot and Immunohistochemistry (IHC). Binding of miR-3614-3p and IGF2BP3 to TRIM25 RNA was verified using luciferase activation assays, RNA immunoprecipitation (RIP) and biotin pull-down assays. In vitro and in vivo loss- and gain-of-function studies were performed to reveal the effects and related mechanism of IGF2BP3-miR-3614-3p-TRIM25 axis in in breast cancer cells proliferation.

We found that an intragenic miRNA-3614-3p inhibits the expression of its host gene TRIM25 by binding to its 3'- untranslated region (UTR). Interestingly, IGF2BP3 can competitively occupy this binding site and inhibit miRNA-3614 maturation, thereby protecting TRIM25 mRNA from miR-3614-mediated degradation. The overexpression of miR-3614-3p dramatically inhibited breast cancer cell growth through the downregulation of TRIM25. Furthermore, the silencing of IGF2BP3 reduced TRIM25 expression, suppressed cell proliferation, and exhibited a synergistic effect with miR-3614-3p overexpression.

Collectively, these results demonstrate that control of TRIM25 RNA by an interplay between IGF2BP3 and miR-3614-3p represents a mechanism for breast cancer cell proliferation. FUND: The scientific research and sharing platform construction project of Shaanxi Province, Opening Project of Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, China Postdoctoral Science Foundation and The National Natural Science Foundation of China.

Adenoid cystic carcinoma of the breast (breast-ACC) is a rare tumor with a favorable prognosis, despite its triple-negative status and special type of basal-like tumor for which scant population-based descriptive data exist. We sought to provide new population-based information on breast-ACC in India. Due to the paucity of the number of cases, the natural history of the disease is not fully understood. This study was undertaken to examine the clinico-pathological characteristics of the disease and to evaluate the outcome of surgical intervention in a tertiary referral care centre.

A retrospective analysis of all patients diagnosed and treated for ACC Breast in our hospital over the past 10 years was carried out (2005-2015). A database of the characteristics of these patients was developed. In all, 14 patients were identified. The investigations performed included routine blood investigations, chest X-ray, bone scan and either an ultrasound or a CT scan.

During the time period of 10 years, of 2347 with breast malignancy admitted to our department, only 14 were diagnosed as having ACC (3.15%). All patients were women (100%). The patients had a median age of 60.7 years (range 37-81). The most common symptom was lump in the breast. Two patients (14.2%) presented with nipple and skin retraction and two patients (14.2%) were asymptomatic with the diagnosis made by an incidental finding on routine examination. The CT and/or magnetic resonance imaging (MRI) showed the typical features of carcinoma breast. All the 14 patients were taken up for surgery. Nine patients underwent Modified radical mastectomy and five patients underwent Breast conservation surgery. Axillary lymph node dissection was carried out in seven patients and sentinel lymph node biopsy in the remaining. Tumor cells had a characteristic histologic pattern of ACC of the breast. Perineural invasion was present in six cases.

ACC of the breast is a very rare malignancy, accounting for less than 0.1% of all breast neoplasms. It affects the left and right breasts equally and tumors arise irrespective of the breast quadrants. However, in about 50 percent of patients, lesions are found in subareolar region. Pain or tenderness described in the minority of cases has not been correlated with histologically-confirmed perineural invasion. ACC is categorized as a basal-like subtype of breast carcinoma. Most cases are macroscopically well-circumscribed. Occasionally, pink, tan, or gray microcysts are evident. A tumor typically consists of a dual-cell population of luminal and myoepithelial-basal cells which may be arranged in one or more of three architectural patterns: tubular-trabecular, cribriform, and solid-basaloid. There is no consensus on the optimal management for patients with ACC of the breast. Based on its indolent clinical course and favorable outcome, ACC of the breast is generally cured by breast-conserving surgery, such as wide excision or quadrantectomy with or without radiotherapy.

Breast-ACC among women is characterized by ER-negative/PR-negative expression, rare regional lymph node involvement, a favorable prognosis with excellent survival, and absence of associated cancers. These findings reinforce the importance of tailored treatments for breast-ACC and the apparent heterogeneity of basal-like breast cancers.

IMP3 is an RNA binding protein required for ribosomal RNA processing, which has been suggested to be a prognostic marker in a large variety of human types of cancer. However, available data on the prevalence of IMP3 expression are largely discrepant. To systematically investigate the epidemiology and clinical relevance of IMP3 expression in human cancers we employed a two-step tissue microarrays (TMAs) approach. First, a normal tissue TMA and a multi-tumor TMA were analyzed for immunohistochemically detectable expression of IMP3 in 76 different normal tissue types and 3889 cancer samples from 95 different tumor categories. In a second step, we searched for associations between IMP3 expression and tumor phenotype and patient prognosis in TMAs containing 697 urinary bladder cancers, 1711 colon cancers, 343 esophageal adenocarcinomas, 251 esophageal squamous cell cancers, 673 lung cancers), 275 pancreatic cancers and 230 stomach cancers. In normal tissues, unequivocal IMP3 expression was found in placenta, lymphocytes and some types of glandular epithelial cells. In cancers, at least one case with weak expression could be found in 76 out of 95 (80%) different tumor types and 64 entities (67%) had at least one tumor with strong positivity. IMP3 expression was most frequently found in testicular cancer (including 71% seminomas and 96% non-seminomas), neuroblastoma (88%), and squamous cell cancer of various origins. Significant associations were found between IMP3 and adverse tumor features in esophageal adenocarcinomas and cancers of the urinary bladder, lung, stomach, and pancreas. In summary, IMP3 was frequently expressed in many different tumor types, and was typically associated with aggressive tumor features.

Adenoid cystic carcinoma (ACC) of the breast is a rare special subtype of breast cancer characterized by the presence of a dual cell population of luminal and basaloid cells arranged in specific growth patterns. Most breast cancers with triple-negative, basal-like breast features (i.e., tumors that are devoid of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, and express basal cell markers) are generally high-grade tumors with an aggressive clinical course. Conversely, while ACCs also display a triple-negative, basal-like phenotype, they are usually low-grade and exhibit an indolent clinical behavior. Many discoveries regarding the molecular and genetic features of the ACC, including a specific chromosomal translocation t(6;9) that results in a MYB-NFIB fusion gene, have been made in recent years. This comprehensive review provides our experience with the ACC of the breast, as well as an overview of clinical, histopathological, and molecular genetic features.

The post-transcriptional control of gene expression mediated by RNA-binding proteins (RBPs), long non-coding RNAs (lncRNAs) as well as miRNAs is essential to determine tumor cell fate and thus is a major determinant in cancerogenesis. The IGF2 mRNA binding protein family (IGF2BPs) comprises three RBPs. Two members of the family, IGF2BP1 and IGF2BP3, are bona fide oncofetal proteins, which are de novo synthesized in various human cancers. In vitro studies revealed that IGF2BPs serve as post-transcriptional fine-tuners modulating the expression of genes implicated in the control of tumor cell proliferation, survival, chemo-resistance and metastasis. Consistently, the expression of both IGF2BP family members was reported to correlate with an overall poor prognosis and metastasis in various human cancers. Due to the fact that most reports used a pan-IGF2BP antibody for studying IGF2BP expression in cancer, paralogue-specific functions can barely be evaluated at present. Nonetheless, the accordance of IGF2BPs' role in promoting an aggressive phenotype of tumor-derived cells in vitro and their upregulated expression in aggressive malignancies provides strong evidence that IGF2BPs are powerful post-transcriptional oncogenes enhancing tumor growth, drug-resistance and metastasis. This suggests IGF2BPs as powerful biomarkers and candidate targets for cancer therapy.

The 2 main prototypes of fibroepithelial tumors of the breast include fibroadenoma and phyllodes tumor (PT). Although both tumors share some overlapping histologic features, there are significant differences in their clinical behavior and management. Phyllodes tumors have been further divided into clinically relevant subtypes, and there is more than one classification scheme for PT currently in use, suggesting a lack of consistency within different practices. Accurate differentiation between fibroadenoma and PT, as well as the grading of PT, may sometimes be challenging on preoperative core needle biopsy. Some immunohistochemical markers have been suggested to aid in the pathologic classification of these lesions.

To discuss the salient histopathologic features of fibroepithelial tumors and review the molecular pathways proposed for the initiation, progression, and metastasis of PTs. Also, to provide an update on immunohistochemical markers that may be useful in their differential diagnosis and outline the practice and experience at our institution from a pathologic perspective.

Sources included published articles from peer-reviewed journals in PubMed (US National Library of Medicine).

Fibroepithelial tumor of the breast is a heterogenous group of lesions ranging from fibroadenoma at the benign end of the spectrum to malignant PT. There are overlapping histologic features among various subtypes, and transformation and progression to a more malignant phenotype may also occur. Given the significant clinical differences within various subtypes, accurate pathologic classification is important for appropriate management. Although some immunohistochemical markers may be useful in this differential diagnosis, histomorphology still remains the gold standard.

Gene expression profiling of breast cancer delineates a particularly aggressive subtype referred to as 'basal-like', which comprises ∼15% of all breast cancers, afflicts younger women and is refractory to endocrine and anti-HER2 therapies. Immunohistochemical surrogate definitions for basal-like breast cancer, such as the clinical ER/PR/HER2 triple-negative phenotype and models incorporating positive expression for CK5 (CK5/6) and/or EGFR are heavily cited. However, many additional biomarkers for basal-like breast cancer have been described in the literature. A parallel comparison of 46 proposed immunohistochemical biomarkers of basal-like breast cancer was performed against a gene expression profile gold standard on a tissue microarray containing 42 basal-like and 80 non-basal-like breast cancer cases. Ki67 and PPH3 were the most sensitive biomarkers (both 92%) positively expressed in the basal-like subtype, whereas CK14, IMP3 and NGFR were the most specific (100%). Among biomarkers surveyed, loss of INPP4B (a negative regulator of phosphatidylinositol signaling) was 61% sensitive and 99% specific with the highest odds ratio (OR) at 108, indicating the strongest association with basal-like breast cancer. Expression of nestin, a common marker of neural progenitor cells that is also associated with the triple-negative/basal-like phenotype and poor breast cancer prognosis, possessed the second highest OR at 29 among the 46 biomarkers surveyed, as well as 54% sensitivity and 96% specificity. As a positively expressed biomarker, nestin possesses technical advantages over INPP4B that make it a more ideal biomarker for identification of basal-like breast cancer. The comprehensive immunohistochemical biomarker survey presented in this study is a necessary step for determining an optimized surrogate immunopanel that best defines basal-like breast cancer in a practical and clinically accessible way.

Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is ubiquitously expressed in embryos, mediating organogenesis, RNA trafficking, and cell growth, and is generally down-regulated in adult tissue. However, IMP3 has recently been shown to be overexpressed in some malignant epithelial neoplasms and to be a useful diagnostic and/or prognostic biomarker for several carcinomas. To determine whether IMP3 might also be an accurate biomarker of Hodgkin lymphoma, we examined 81 Hodgkin lymphomas for immunoreactivity to IMP3 as compared to commonly used markers such as CD30, CD15, PAX5, and MUM1. Consequently, in 98.8% (80/81) of Hodgkin lymphomas, the malignant Hodgkin and Reed-Sternberg cells were selectively reactive for IMP3, with 72.8% (59/81) of the tumors showing strong, diffuse cytoplasmic staining. Positive staining of the Hodgkin lymphomas was also seen for CD30 (82.7%, 67/81), CD15 (65.4%, 53/81), PAX5 (84.0%, 68/81), and MUM1 85.2% (69/81), but significantly fewer cells showed strong staining intensity for CD30 (32.1%, 26/81), CD15 (17.3%, 14/81), PAX5 (12.3%, 10/81), and MUM1 (29.6%, 24/81). Furthermore, the IMP3 staining was selectively restricted to Hodgkin and Reed-Sternberg cells, with a clearly negative background, and complementary to CD30 staining. Our findings show that IMP3 may be a useful diagnostic marker of Hodgkin lymphoma, helping to improve diagnostic accuracy for this malignancy.

Epithelial-myoepithelial proliferations of the breast are a heterogeneous poorly defined group of lesions characterized morphologically by dual differentiation into ductal (luminal) and myoepithelial cells. They include neoplastic and non-neoplastic entities that have overlapping morphologic features that may give rise to diagnostic difficulty. Many of these entities are low grade or of uncertain malignant potential but the biology of some of these rare lesions remains to be elucidated. This article discusses the differential diagnosis of epithelial-myoepithelial lesions of the breast and highlights the morphologic features of some of these entities.