Histology and histopathology Vol.28, nº 9 (2013)
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- PublicationOpen AccessExercise preconditioning reduces acute ischemic renal injury in Hsp70.1 knockout mouse(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Lee, Jin; Park, Sok; Kim, Won KyuBackgroun/aims: Heat shock protein 70 (Hsp70) is an anti-apoptotic protein that has a protective effect in renal ischemic injury. Exercise up-regulates Hsp family proteins (Hsps), antioxidants and antiapoptotic proteins. We hypothesized that exercise as preconditioning could attenuate acute renal dysfunction and apoptosis resulting from renal ischemic injury under the Hsp70 deficient circumstance and could contribute to the prevention of renal injury induced by ischemia. Method: To investigate the effect of exercise preconditioning on protecting the kidney from ischemia in Hsp70 deficiency, we measured apoptosis-related factors and Hsps. Hsp70.1 KO and wild-type mice were divided into sham control (Sham), exercise preconditioning (Ex), renal ischemia-after-exercise (Ex+IR), and ischemia (IR) groups. Where appropriate a treadmill exercise was performed at 20 m/min, 60 min per day on a 0% gradient for 7 days, and renal ischemia was induced by clamping the renal pedicle for 25 min. To characterize the effects of exercise on oxidative stress- and apoptosis-related factors, and Hsp27 and 70 expressions, we performed immunohistochemistry, western blotting and TUNEL assay, and also measured level of serum creatinine. Results: Serum creatinine concentration and 4-HNE expression were raised in the IR group, as were caspases 3, 7 and 9, while Cu- and Mn-SOD levels were reduced, as were those of anti-apoptotic proteins Bcl-XL, Bcl-2 and Hsp27. All these effects were largely reversed by the exercise preconditioning, as was the decrease in apoptotic cells observed after exercise preconditioning. Conclusion: Exercise preconditioning has a beneficial effect in inhibiting oxidative stress and apoptotic cell death in the kidney resulting from ischemic injury even under Hsp70 deficiency.
- PublicationOpen AccessExpression of claudins relates to tumour aggressivity, location and recurrence in ependymomas(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Nordfors, K.; Haapasalo, J.; Sallinen, P. K.; Haapasalo, H.; Soini, Y.The aim of our study was to assess the nature and importance of claudin expression in grade I-III ependymomas. The expression of claudins 2-5, 7, 10, TWIST, and ZEB1 were investigated in a series of 61 ependymomas using immunohistochemistry. All the claudins were expressed in ependymomas, except for CLDN4. CLDN5 positive tumours were associated with higher grade (p=0.049), whereas CLDN10 was lower in higher grade tumours (p=0.039). CLDN5 and CLDN3 were overexpressed in ependymomas of cerebral location (p=0.036, p=0.007, respectively). CLDN5 positive tumours showed more nuclear atypia, endothelial proliferation, mitosis, and hypercellularity (p=0.007, p=0.018, p=0.041, p=0.010, respectively). CLDN5 positivity correlated to higher proliferation (p=0.015). CLDN7 was more often positive in primary tumours (p=0.041). Positive ZEB1 expression was associated with CLDN2 negativity (p=0.031). TWIST-negative tumours were more often also CLDN5 and 10 negative (p=0.013, p=0.017, respectively). CLDN5 was related to more aggressive tumours compared to CLDN2 and 10, which tended to display a better degree of differentiation and a better prognosis. CLDN2 and CLDN5 were expressed commonly in ependymomas, while the parental ependymal cells in the central nervous system were usually negative. Evidently, claudins influence growth and differentiation in ependymomas.
- PublicationOpen AccessBeta-catenin and survivin expression in keratocystic odontogenic tumor (KCOT). A comparative immunohistochemical study in primary, recurrent and nevoid basal cell carcinoma syndrome (NBCCS)-associated lesions(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Leonardi, Rosalia; Matthews, J.B.; Loreto, Carla; Musumeci, Giuseppe; Campisi, G.; Lo Muzio, L.; Dos Santos, J.N.; Pastorino, L.; Bufo, P.; Pannone, G.Aim: To determine the epithelial expression of ß-catenin and survivin in sporadic (primary, and recurrent) and nevoid basal cell carcinoma syndrome (NBCCS) keratocystic odontogenic tumour (KCOT) in order to assess activation of the ß-catenin pathway and evidence of apoptotic inhibition, processes that may contribute to the known differences in their biological behaviour. Materials and Methods: Sections from 40 cases of KCOT (19 sporadic/primary; 9 sporadic/recurrent and 12 NBCCS-associated) were immunohistochemically stained for ß-catenin and survivin. The extent and intensity of immunoreactivity within the lining epithelium was assessed, using semi-quantitative scales, independently by two pathologists who were blinded to the clinical-pathological data. Data were analysed using Kruskal-Wallis test and, for pair-wise comparisons, Mann-Whitney test with Bonferroni correction. Results: All cystic epithelial linings stained for ß- catenin and survivin but there were differences in the pattern and intensity of staining among KCOT types. Sporadic primary KCOT showed weaker staining for ß- catenin (P=0.0003) and survivin (P<0.0048) that was restricted to the basal and para-basal layers only, compared to sporadic recurrent and NBCCS-associated KCOT, which showed expression throughout all epithelial layers. There were no differences in ß-catenin expression among recurrent and NBCCS-associated KCOT, whereas the intensity of survivin staining was higher in NBCCS-KCOT (P=0.0003). Nuclear staining for ß-catenin was found exclusively in recurrent (5/9 cases) and NBCCS-associated (4/12 cases) KCOT. Conclusion: The data demonstrate ß-catenin delocalization and survivin over-expression in recurrent sporadic and NBCCS-associated KCOT suggesting that these pathways are related to apoptotic inhibition have a role in KCOT growth and recurrence.
- PublicationOpen AccessBag-3 expression is involved in pathogenesis and progression of colorectal carcinomas(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Yang, Xue; Tian, Zhong; Gou, Wen-feng; Takahashi, Hiroyuki; Xing, Ya-nan; Takano, Yasuo; Zheng, Hua-ChuanBcl-2-associated athanogene 3 (Bag-3) belongs to a member of the Hsc70 binding co-chaperone Bag-family proteins and has critical roles in protein homeostasis, cell survival, actin organization, cell adhesion, cell motility and tumor metastasis. To clarify the role of Bag-3 in colorectal carcinogenesis and subsequent development, its expression was examined by immunohistochemistry (IHC) and in situ hybridization (ISH) on tissue microarrays containing colorectal carcinomas, adenomas, non-neoplastic mucosa (NNM) and metastatic carcinomas in lymph node and liver. Colorectal carcinoma tissue and cell lines were studied for Bag-3 expression by RT-PCR, Western blot and immunofluorescence. The results demonstrated that Bag3 was distinctly expressed in Colo201, Colo205, DLD-1, HCT-15, HCT-116, HT-29, KM-12, SW480, SW620, and WiDr at both mRNA and protein levels. Carcinoma showed stronger Bag-3 expression than adjacent NNM by IHC and Western blot (P<0.05), while its mRNA had the opposite by real-time PCR and ISH (P<0.05). Metastatic carcinoma more frequently expressed Bag-3 mRNA in lymph node and liver than in primary carcinoma (P<0.05). Immunohistochemically, Bag-3 expression was seen to gradually decrease from carcinoma, adenoma to NNM (P<0.05). There was a positive correlation between Bag-3 expression and TNM staging and GRP94 expression (P<0.05), but no relationship to patient age or sex, tumor size, depth of invasion, lymphatic or venous invasion, lymph node metastasis, differentiation or prognosis of colorectal carcinomas (P>0.05). Our study indicated that aberrant Bag-3 expression might be involved in colorectal adenoma-adenocarcinoma sequence and subsequent progression.
- PublicationOpen AccessRANKL is downregulated in bone cells by physical activity (treadmill and vibration stimulation training) in rat with glucocorticoid-induced osteoporosis(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Pichler, Karin; Loreto, Carla; Leonardi, Rosalia; Reuber, Tobias; Weinberg, Annelie Martina; Musumeci, GiuseppeThe aim of this study was to investigate bone tissue and plasma levels of RANKL and OPG in rats with prednisolone-induced osteoporosis and to evaluate the outcomes of physical activity on the skeletal system by treadmill and vibration platform training. Osteoporosis is a disease characterised by low bone mass and structural deterioration of bone tissue leading to bone fragility. Vibration exercise is a new and effective measure to prevent muscular atrophy and osteoporosis. The animals were divided into 5 groups. 1: control rats; 2: rats with osteoporosis receiving prednisolone; 3: rats receiving prednisolone and treadmill training; 4: rats receiving prednisolone and vibration stimulation training; 5: rats receiving prednisolone, treadmill and vibration stimulation training. For bone evaluations we used whole-body scans, histology and histomorphometric analysis. RANKL and OPG expression was evaluated by immunohistochemistry and biochemical analysis. After treatment, our data demonstrated that RANKL expression was significantly increased in groups 2 and 3 and decreased in groups 4 and 5. Conversely, OPG expression was significantly decreased in groups 2 and 3 and increased in groups 4 and 5. In conclusion, our findings suggest that mechanical stimulation inhibits the activity of RANKL. This finding provides new insights into the occurrence and progression of osteoporosis.
- PublicationOpen AccessCommonly used mesenchymal stem cell markers and tracking labels: Limitations and challenges(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Lin, Ching-Shwun; Xin, Zhong-Cheng; Dai, Jican; Lue, Tom F.Early observations that cultured mesenchymal stem cells (MSCs) could be induced to exhibit certain characteristics of osteocytes and chondrocytes led to the proposal that they could be transplanted for tissue repair through cellular differentiation. Therefore, many subsequent preclinical studies with transplanted MSCs have strived to demonstrate that cellular differentiation was the underlying mechanism for the therapeutic effect. These studies generally followed the minimal criteria set by The International Society for Cellular Therapy in assuring MSC identity by using CD70, CD90, and CD105 as positive markers and CD34 as a negative marker. However, the three positive markers are co-expressed in a wide variety of cells, and therefore, even when used in combination, they are certainly incapable of identifying MSCs in vivo. Another frequently used MSC marker, Stro-1, has been shown to be an endothelial antigen and whether it can identify MSCs in vivo remains unknown. On the other hand, the proposed negative marker CD34 has increasingly been shown to be expressed in native MSCs, such as in the adipose tissue. It has also helped establish that MSCs are likely vascular stem cells (VSCs) that reside in the capillaries and in the adventitia of larger blood vessels. These cells do not express CD31, CD104b, or α-SMA, and therefore are designated as CD34+CD31-CD140b-SMA-. Many preclinical MSC transplantation studies have also attempted to demonstrate cellular differentiation by using labeled MSCs. However, all commonly used labels have shortcomings that often complicate data interpretation. The ß-gal (LacZ) gene as a label is problematic because many mammalian tissues have endogenous ß-gal activities. The GFP gene is similarly problematic because many mammalian tissues are endogenously fluorescent. The cell membrane label DiI can be adsorbed by host cells, and nuclear stains Hoechst dyes and DAPI can be transferred to host cells. Thymidine analog BrdU is associated with loss of cellular protein antigenicity due to harsh histological conditions. Newer thymidine analog EdU is easier to detect by chemical reaction to azide-conjugated Alexa fluors, but certain bone marrow cells are reactive to these fluors in the absence of EdU. These caveats need to be taken into consideration when designing or interpreting MSC transplantation experiments.
- PublicationOpen AccessPrognostic value of CXCR4 expression in patients with clear cell renal cell carcinoma(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Li, Guorong; Badin, Grégory; Zhao, An; Gentil-Perret, Anne; Tostain, Jacques; Péoc’h, Michel; Gigante, MarcIntroduction: The expression of CXCR4 is implicated in the metastatic dissemination of different cancers. The information on its prognostic value has been very limited in clear cell renal cell carcinoma (ccRCC). Our objective was to explore the prognostic value of CXCR4 in ccRCC. Materials and methods: 104 patients with a ccRCC were studied. There were 69 men and 35 women with an average age of 64.5 years old (range: 34-86 years). The CXCR4 expression was evaluated by immunohistochemistry. The follow-up varied from 12 to 184 months with a mean of 79.5 months. Kaplan-Meier with a log rank test was performed to compare overall survival and cancerspecific survival after surgery. Univariate and multivariate analyses were performed according to the Cox regression model. Results: CXCR4 expression was found in 68/104 (65.4%) of tumor samples. CXCR4 expression was located in the nucleus in 55/68 (80.8%) cases while cytoplasm or membrane location was found in 13/68 (19.2%) cases. High expression was found in 25/68 (36.8%) cases. During follow-up, 39 patients died, of which 26 died of cancer. Kaplan-Meier analysis revealed that a high expression of CXCR4 was associated with a reduced overall survival (p=0.017) and cancer-specific survival (p=0.022). Univariate analysis indicated that a high expression of CXCR4 was a significant factor for a poorer overall survival (p=0.020) and cancer-specific survival (p=0.027). By multivariate analysis, a high expression of CXCR4 appeared to be an independent factor of overall survival (p=0.024) and cancer-specific survival (p=0.028). Conclusion: This study suggested that a high CXCR4 expression was correlated with a worse outcome for ccRCC patients.
- PublicationOpen AccessHu/elav RNA-binding protein HuR regulates parathyroid hormone related peptide expression in human lung adenocarcinoma cells(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Lauriola, Libero; Serini, Simona; Granone, Pierluigi; Lanza, Paola; Martini, Maurizio; Calviello, Gabriella; Oreste Ranelletti, FrancoIn 54 stage I and II human lung adenocarcinomas, HuR and PTHrP levels were positively correlated and the PTHrP-HuR status of the tumor was an independent prognostic marker of the clinical outcomes of patients. The possibility that HuR could upregulate PTHrP expression in lung adenocarcinoma was investigated by immunohistochemical, Western blot and RT-PCR analyses in HCC44 and DV90 human lung adenocarcinoma cell lines. In both cell lines, knockdown of HuR by specific siRNAs reduced PTHrP mRNAs and both cellular and secreted protein. Moreover, it inhibited cell growth and induced cell apoptosis, as revealed by the increase of caspase-3 activity. These effects were partially rescued by the addition of exogenous PTHrP (1-34). Analysis by actinomycin D assay revealed that in both cell lines HuR silencing produced a decrease of PTHrP mRNA half-life by about 70%. These findings add PTHrP to the list of lung cancer-associated genes, whose mRNA is stabilized by HuR.
- PublicationOpen AccessExpression of vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2 in primary and recurrent WHO grade III meningiomas(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Baumgarten, Peter; Brokinkel, Benjamin; Zinke, Jenny; Zachskorn, Cornelia; Ebel, Heinrich; Albert, Friedrich K.; Stummer, Walter; Plate, Karl H.; Harter, Patrick N.; Hasselblatt, Martin; Mittelbronn, MichelWHO grade III meningiomas are malignant neoplasms for which new and more targeted treatment strategies are urgently needed. Although clinical trials investigating anti-angiogenic vascular endothelial growth factor (VEGF) targeted therapies are currently recruiting, knowledge about the expression of VEGF and VEGF receptors remains to be determined. Methods: We investigated the expression of VEGF and its receptors VEGFR1 and VEGFR2 in 32 WHO grade III meningioma samples by immunohistochemistry. Furthermore, we performed in-situ hybridisation for VEGF. Results: We found low VEGF expression in tumor and endothelial cells. Highest VEGF expression levels were seen in peri-necrotic tumor cells potentially suffering from hypoxia. VEGFR1 and 2 were virtually absent on tumor cells, although endothelial cells displayed significantly higher levels reaching stronger expression for VEGFR2 than VEGFR1. Conclusions: Our findings showing constant expression levels of VEGFR2 in endothelial cells serve as a first indication that the use of small tyrosine kinase inhibitors such as Sunitinib directly targeting the VEGF-receptors might be worth testing, also in the clincial context in cases of therapy-refractory meningiomas. Further investigations are needed to study the response to drugs targeting the VEGF pathway in relation to the expression profile of VEGF and its receptors in high grade meningiomas.
- PublicationOpen AccessClinicopathological characteristics and prognosis of Chinese patients with sarcomatoid carcinoma of the bladder(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Guo, Ai T.; Huang, Heng; We, Li X.Objectives: The purpose of this study was to retrospectively analyze the clinicopathological features and prognosis of Chinese patients diagnosed with sarcomatoid carcinoma (SC) of the bladder. Methods: 13 patients admitted to the General Hospital of People’s Liberation Army (PLA) between 1999 and 2010 (study group) and 74 Chinese patients diagnosed between 1994 and 2010 and reported in one of two Chinese databases (literature group). Results: The two groups were similar in all demographic and clinical characteristics except depth of tumor invasion. SC of the bladder was most common in older males and most patients had high-grade or latestage disease at diagnosis. The 6-month, 1-year, 2-year, and 5-years survival rates were 78.9%, 42.7%, 28.0%, and 21.0%, respectively. Analysis of the association of demographic and clinical characteristics with prognosis indicated no significant effect of sex, age, lesion location, tumor diameter, tumor type, depth of invasion, type of surgery, gross hematuria, and urinary tract infection. Conclusions: Our results suggest that the pathologic tumor stage was unrelated to prognosis. Early diagnosis and surgical intervention are preferred strategies for improvement of prognosis. The association between clinical stage and survival time requires further analysis.
- PublicationOpen AccessHirschsprung’s disease as a model of complex genetic etiology(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Borrego, Salud; Ruiz-Ferrer, Macarena; Fernández, Raquel M.; Antiñolo, GuillermoHirschsprung disease (HSCR), or aganglionic megacolon, is a developmental disorder characterised by the absence of ganglion cells along variable length of the distal gastrointestinal tract, leading to the most common form of functional intestinal obstruction in neonates and children. Aganglionosis is attributed to a failure of neural crest cells to migrate, proliferate, differentiate or survive during enteric nervous system (ENS) development in the embryonic stage. The incidence of HSCR is estimated at 1/5000 live births and most commonly presents sporadically with reduced penetrance and male predominance, although it can be familial and may be inherited as autosomal dominant or autosomal recessive. In 70% of cases, HSCR occurs as an isolated trait and in the other 30% HSCR is associated with other congenital malformation syndromes. HSCR has a complex genetic etiology with several genes and loci being described as associated with either isolated or syndromic forms. These genes encode for receptors, ligands (especially those participating in the RET and EDNRB signaling transduction pathways), transcriptional factors or other cell elements that are usually involved in the neural crest cell development and migration that give rise to ENS. Nevertheless, the RET proto-oncogene is considered the major disease causing gene in HSCR. A common RET variant within the conserved transcriptional enhancer sequence in intron 1 has been shown to be associated with a great proportion of sporadic cases and could act as a modifier by modulating the penetrance of mutations in other genes and possibly of those mutations in the RET proto-oncogene itself.
- PublicationOpen AccessChanged lineage composition is an early event in breast carcinogenesis(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Hilton, Heidi N.; Kantimm, Silke; Graham, J. Dinny; Clarke, Christine L.The epithelium compartment of the human breast is made up of a branching ductal-lobular system, which is lined by a single layer of luminal epithelial cells surrounded by contractile myoepithelial cells. The coordinated development of these two cell types, and maintenance of their relative proportions, is fundamentally important for normal breast morphogenesis. Changes in cell type composition is one of the hallmark features of breast cancer progression, and the vast majority of breast tumors are comprised of luminal cells only, with a complete absence of myoepithelial cells. Despite this striking alteration in relative proportions of luminal and myoepithelial cells in invasive breast cancers compared with normal breast tissue, the steps in this dramatic change in cellular composition remain poorly characterised, nor is it known whether loss of myoepithelial cells is an early event in carcinogenesis. In a panel of breast tissues, we quantitated the proportion of luminal cells relative to the surrounding myoepithelial cell layer in a panel of normal and pre-invasive breast tissue samples, including lesions with proliferative disease without atypia (PDWA), columnar cell lesions (CCL), atypical ductal hyperplasia (ADH), and DCIS, and correlated these findings with proliferation in the same lesions. The study findings showed that changes in lineage composition correlate with increased proliferation, and are one of the earliest events in breast carcinogenesis. Therefore not only are myoepithelial cells important in distinguishing between invasive and non-invasive tumors, their relative proportion compared with luminal cell numbers may provide a new potential indicator of which premalignant lesions are at higher risk of progression to invasive disease.
- PublicationOpen AccessDysfunction of protein homeostasis in myotonic dystrophies(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Meola, Giovanni; Jones, Karlie; Wei, Christina; Timchenko, Lubov T.Neuromuscular diseases Myotonic Dystrophies type 1 and type 2 (DM1 and DM2) are caused by unstable CTG and CCTG repeat expansions and have highly complex molecular mechanisms. DM1 is caused by the expansion of CTG repeats in the 3’ UTR of the gene coding for Dystrophia Myotonica-Protein Kinase (DMPK). In DM2, intronic CCTG repeats are located in a gene encoding the Zinc Finger Protein 9 (ZNF9, also known as Cellular Nucleic Acid Binding Protein, CNBP). Both expansions cause pathologies through RNA CUG and CCUG repeats, which have toxic effects on the processing of many RNAs in the patients’ tissues. The pathogenic role of CUG and CCUG repeats in the mis-regulation of alternative splicing, mediated by RNA-binding proteins CUGBP1 and MBNL1, has been discussed in a number of excellent reviews. Recent reports suggest that mutant RNA repeats affect several other RNA-binding proteins such as Staufen1 and the DEAD-box RNA helicase p68 (DDX5). Since CUGBP1, Staufen1 and p68 have many functions in cytoplasm, including regulation of protein translation, it is predicted that the alterations of these proteins in DM cells might have a toxic effect on global protein turnover. In this mini-review, we will summarize observations showing the role of RNA-binding proteins, CUGBP1 and ZNF9, in protein turnover in DM1 and in DM2. We will also discuss a possible role of misbalanced protein turnover in the age-dependent progression of DM1 and in a late onset of DM2.
- PublicationOpen AccessMicroglandular adenosis: a non-obligate precursor of triple-negative breast cancer?(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Wen, Yong Hannah; Weigelt, Britta; Reis-Filho, Jorge S.Microglandular adenosis is a rare glandular lesion of the breast, which can mimic well-differentiated invasive carcinoma, and is characterized by a haphazard proliferation of uniform small round glands with open lumina and lacking a myoepithelial cell layer. This lesion has a rather unique immunohistochemical profile characterized by expression of cytokeratins and S-100, and lack of estrogen receptor (ER) and progesterone receptor (PR). The role of microglandular adenosis as a potential precursor of invasive breast cancer has long been a matter of controversy; however, recent molecular analyses have demonstrated that these lesions are heterogeneous at the genetic level, and that at least a subset of microglandular adenosis are clonal and display gene copy number alterations. Importantly, the pattern of genetic aberrations found in microglandular adenosis differs from that of other non-obligate precursors of ER-positive breast cancer. Carcinomas arising in microglandular adenosis are mostly of triple-negative phenotype (i.e. lack of ER, PR and HER2) and express S100, similar to microglandular adenosis. Genetic alterations found in microglandular adenosis have been shown to be similar to those found in synchronous invasive carcinomas. Here we review the clinical, morphological, and molecular features of microglandular adenosis, with an emphasis on its role as a non-obligate precursor of triple-negative breast cancer, and discuss areas for future research endeavors to clarify the clinical and biological significance of these fascinating lesions.