Mammary Neoplasia Research Articles

Associations Between Dog Breed and Clinical Features of Mammary Epithelial Neoplasia in Bitches: an Epidemiological Study of Submissions to a Single Diagnostic Pathology Centre Between 2008–2021

Mammary cancer is one of the most common neoplasms of dogs, primarily bitches. While studies have been carried out identifying differing risk of mammary neoplasia in different dog breeds, few studies have reported associations between dog breeds and clinical features such as number of neoplastic lesions found in an individual case or the likelihood of lesions being benign or malignant. Such epidemiological studies are essential as a foundation for exploring potential genetic drivers of mammary tumour behaviour. Here, we have examined associations between breed, age and neuter status and the odds of a diagnosis of a mammary epithelial-origin neoplastic lesion (as opposed to any other histopathological diagnosis from a biopsied lesion) as well as the odds of a bitch presenting with either a single mammary lesion or multiple lesions, and the odds that those lesions are benign or malignant. The study population consisted of 129,258 samples from bitches, including 13,401 mammary epithelial neoplasms, submitted for histological assessment to a single histopathology laboratory between 2008 and 2021.In multivariable analysis, breed, age and neuter status were all significantly associated with the odds of a diagnosis of a mammary epithelial-origin neoplastic lesion. Smaller breeds were more likely to receive such a diagnosis. In cases diagnosed with a mammary epithelial neoplasm, these three factors were also significantly associated with the odds of diagnosis with a malignant lesion and of diagnosis with multiple lesions. Notably, while neutered animals were less likely to have a mammary epithelial neoplasm diagnosed, and were less likely to have multiple neoplasms, they were more likely to have malignant disease. Exploration of the patterns of risk of developing malignant disease, or multiple lesions, across individual breeds showed no breed with increased odds of both outcomes. Breeds with altered odds compared to the Crossbreed baseline were either at increased risk of malignant disease and decreased risk of multiple lesions, or vice versa, or they were at significantly altered odds of one outcome with no change in the other outcome. Our analysis supports the hypothesis that age, neuter status and intrinsic biological and genetic factors all combine to influence the biological heterogeneity of canine mammary neoplasia.

Goats diagnosed with neoplasia display variability in clinical presentations, treatments, and outcomes.

To describe clinical presentation, treatment, and short- and long-term outcomes of goats diagnosed with neoplasia. 46 goats with a definitive diagnosis of ≥ 1 neoplastic process admitted over a 15-year period. Medical records for all goats admitted to the Colorado State University Veterinary Teaching Hospital over a 15-year period were reviewed to identify animals diagnosed with neoplasia. Signalment, presenting complaint, duration of clinical signs, diagnostic testing, treatment, and short-term outcomes were recorded. When available, long-term follow-up data were collected via email or telephone interview with owners. 46 goats with 58 neoplasms were identified. The prevalence of neoplasia within the study population was 3.2%. The most commonly diagnosed neoplasms were squamous cell carcinoma, thymoma, and mammary carcinoma. The Saanen breed was the most common breed noted in the study population. Evidence of metastasis was found in 7% of the goats. Long-term follow-up was available in 5 goats with mammary neoplasia that underwent bilateral mastectomy. No evidence of mass regrowth or metastasis was noted in any of the goats 5 to 34 months postoperatively. Goats are increasingly treated as companion rather than strictly production animals, making it important for veterinarians to provide more evidence-based and advanced clinical care. This study provided a clinical overview of presentation, treatment, and outcome for goats diagnosed with neoplasia and highlighted the challenges associated with the wide variety of neoplastic processes affecting goats.

Parameters of Metabolic Response to Surgical Trauma Induced via Unilateral Total Mastectomy Associated or Not to Ovariohysterectomy in Dogs.

Surgical excision of solid tumors is required for local control of neoplasms. However, surgical trauma can stimulate the release of proangiogenic growth factors, suppressing cell-mediated immunity and favoring the development of micrometastases and progression of residual disease. The present study aimed to evaluate the intensity of the metabolic response to trauma induced via unilateral mastectomy in bitches with mammary neoplasia, the consequences of its joint performance with ovariohysterectomy, and their respective effects on the organic response. Two groups of animals were evaluated in seven perioperative moments, namely, unilateral mastectomy (G1) and unilateral mastectomy associated with ovariohysterectomy (G2). Thirty-two female dogs were selected, ten clinically healthy, and twenty-two diagnosed with mammary neoplasia. Surgical trauma reduced serum concentrations of albumin and interleukin-2 but increased blood levels of glucose and interleukin-6 in the postoperative of G1 and G2 patients. Moreover, serum cortisol levels increased after unilateral mastectomy associated with ovariohysterectomy. Our findings allowed us to conclude that unilateral mastectomy induces significant metabolic alterations in female dogs with mammary neoplasms and its joint performance with ovariohysterectomy increases the organic response to trauma.

PIK3CA is recurrently mutated in canine mammary tumors, similarly to in human mammary neoplasia

Biological features of neoplastic disease affecting mammary gland tissue are shared between canines and humans. Research performed in either species has translational value and early phase clinical trials performed in canines with spontaneous disease could be informative for human trials. The purpose of this study was to investigate the somatic genetic aberrations occurring in canine mammary neoplasia by exome capture and next generation sequencing. Based on 55 tumor-normal pairs we identified the PIK3CA gene as the most commonly mutated gene in canine mammary tumors, with 25% of samples carrying mutations in this gene. A recurrent missense mutation was identified, p.H1047R, which is homologous to the human PIK3CA hotspot mutation found in different types of breast neoplasia. Mutations homologous to other known human mutation hotspots such as the PIK3CA p.E545K and the KRAS p.G12V/D were also identified. We identified copy number aberrations affecting important tumor suppressor and oncogenic pathways including deletions affecting the PTEN tumor suppressor gene. We suggest that activation of the KRAS or PIK3CA oncogenes or loss of the PTEN suppressor gene may be important for mammary tumor development in dogs. This data endorses the conservation of cancer across species and the validity of studying cancer in non-human species.

Ultrassonografia modo-B e Doppler dos rins de cadelas com neoplasias mamárias submetidas à quimioterapia adjuvante

ABSTRACT: Mammary neoplasia represents the most frequently diagnosed type of neoplasia in bitches. Although surgical removal is the procedure of choice for therapeutic management, chemotherapy protocols appear as important allies and adjuvants. Despite the great advances that have occurred in the field of cancer therapy, the systemic repercussions of these drugs still impose important limitations on their use. In this sense, the development of increasingly targeted therapeutic protocols and preventive monitoring of patients represent important strategies to avoid possible complications - among them, Acute Kidney Injury (AKI). Routinely, ultrasound evaluation is used to identify morphological or metastatic variations in abdominal cavity organs. Acting complementary to the B-mode evaluation, Doppler mapping proves to be efficient in recognizing alterations in vascular hemodynamics. Therefore, the objective of the present study was to evaluate the use of B-mode and Doppler ultrasound to identify renal morphological and hemodynamic alterations in bitches with mammary neoplasia submitted to adjuvant chemotherapy protocols that associate gemcitabine with carboplatin. Thirteen bitches were included, without distinction of breed and between seven and 13 years of age. The animals were evaluated ultrasonographically at two different times during three consecutive chemotherapy cycles: before (T0) and one and a half hours after each cycle (T1), for 42 days. No morphological changes were observed in B-mode throughout the chemotherapy protocol. However, the Doppler velocimetry indices demonstrated statistical differences before (T0) and after (T1) the administration of the drugs. It was concluded that Doppler ultrasound could be used as a complementary method for monitoring the renal response of patients exposed to nephrotoxic drugs and potentially causing renal injury.

Canine mixed tumors as one of the mammary neoplasia varieties

The most significant interest in veterinary oncology is occupied by tumors of a mixed nature, which are represented by the direct interaction of epithelial and mesenchymal components. According to some data, the formation of cell lineage of mesenchymal cells occurs due to the transformation of epidermal basket cells surrounding the glandular epithelium. In this case, the formation of a cartilage anlage with its further transformation into differentiated bone tissue occurs. The article contains information about the structure and features of the location and interaction of mixed tumors’ glandular and stromal components in female dogs (n=29). It was revealed that in addition to simple mixed neoplasms, tumors with proplasia of the mesenchymal component into highly differentiated cartilage or bone tissue were also often registered. To confirm subcellular changes in the expression of certain types of proteins, such as a-SMA and vimentin, an IHC study was used. The expression of the studied biomarkers was established in mesenchymal fibroblastic differon cells and myoepithelial cells. The intensity of immunoreactive material expression ranged from moderate (2+) to strong (3+), indicating changes in myoepithelial cells’ genotype during the formation of mixed mammary neoplasms.

Neoplasia mamaria en perras: Revisión

The increased life expectancy of animals increases the incidence of neoplasms. Mammary neoplasia is among the most common diseases in dogs. In 35 to 50% of female dogs, breast tumors are malignant. The major importance of malignant neoplasms is the ability to generate metastasis, as the possibility of death increases. Clinical staging is part of cancer care, and aims to stipulate the prognosis and the best treatment. The sentinel lymph node comprises the first lymph node to drain tumor cells, and from there it can be distributed to other organs. Knowing the importance of breast cancer, this study aims to review the main aspects of this condition in bitches, as well as prognosis, treatments and adjuvant therapies.

Abstract A017: Epigenetic activation of SOX11 is associated with recurrence and progression of DCIS to invasive breast cancer

Abstract Background: Screening mammography has dramatically increased incidental detection of Ductal Carcinoma in situ (DCIS), a non-obligate precursor of breast cancer. Approximately 10-50% of DCIS progress to the invasive disease and the risk of developing recurrence or progression after surgery is still not well defined based on clinical and pathological characteristics. Our study investigated the genetic and epigenetic mechanisms associated with recurrence and progression of DCIS to invasive cancer. Methods: To identify genes associated with recurrence and progression of DCIS to invasive cancer, we performed Nanostring nCounter analysis (MDACC, n = 40) and RNA-sequencing (Sloane study, n = 183) in two independent prospective primary DCIS cohorts. Mammary epithelial-specific Pten knockout mouse model developed in our lab was used to interrogate the genetic pathway deregulated during development of mammary intraepithelial neoplasia to adenocarcinoma. ATAC-seq and ChIP-qPCR were performed to assess chromatin accessibility in the genome and validate binding of histone-modifying enzymes on target promoters. Histopathological analyses were performed to determine DCIS grades, subtypes, and protein expression profiles. Results: RNA expression profiles of normal mammary and primary DCIS tissues (n = 40) identified 10 gene transcripts that were significantly and differentially expressed between normal and high-grade DCIS. Only SOX11 expression was significantly and progressively correlated with KI67 and the DCIS recurrence score as described by Solin (JNCI 2013). Mammary intraepithelial neoplasia in Pten knockout mice and 21T DCIS to IDC progression cell line model also revealed SOX11 upregulation compared to controls. Since PTEN/PI3K/AKT pathway is known to regulate global active histone marks and open accessible chromatin, we investigated the role of AKT on SOX11 expression. Results demonstrated that inhibition of AKT altered enrichment of histone-modifying enzymes KDM5A and EZH2 on the promoter accompanying downregulated SOX11 expression in DCIS cell lines. SOX11 and EZH2 expression profiles revealed significant correlation in DCIS tissue samples. In two independent DCIS cohorts, SOX11 was found significantly upregulated in HER2+ and basal-like DCIS subtypes (P < 0.001). RNA sequencing in 183 longitudinal DCIS cases of the Sloane study (median follow-up of 96 months) revealed significantly shorter recurrence-free survival in SOX11+ than SOX11- patients (P < 0.02 in all subtypes; P = 0.002 in HER2+ subtype). Based on COX proportional hazards model, SOX11 alone was significantly associated with the risk of developing recurrence and invasive breast cancer (HR = 1.7, 95% CI = 1.1 to 2.6; P < 0.02). Conclusions: Epigenetic activation of SOX11 is associated with recurrence and progression of DCIS to invasive breast cancer. SOX11 and its epigenetic regulators can be developed as prognostic markers for DCIS patients with recurrence risk independent of traditional clinical and pathologic characteristics. Citation Format: Warapen Treekitkarnmongkol, Vandna Shah, Kazuharu Kai, Hiroshi Katayama, Justin W. Wong, Farah A Ladha, Brian Menegaz, Sarah E. Pinder, Wei Lu, Fei Yang, Ximing Tang, Savitri Krishnamurthy, Ignacio I. Wistuba, Elinor J. Sawyer, Alastair M. Thompson, Subrata Sen. Epigenetic activation of SOX11 is associated with recurrence and progression of DCIS to invasive breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr A017.

Protein Expression of PI3K/AKT/mTOR Pathway Targets Validated by Gene Expression and its Correlation with Prognosis in Canine Mammary Cancer.

Mammary cancer is the main type of neoplasia in female dogs and is considered an adequate model for the biological and therapeutic study of cancer in women. The PIK3CA/AKT/mTOR pathway plays a central role in cellular homeostasis and is often dysregulated in cancer. The increased expression of PI3K protein in the literature is associated with a poor prognosis, and alterations in the PIK3CA gene can lead to changes in downstream pathways. Thus, the objective of this study was to validate the protein expression to confirm the gene expression of proteins belonging to the main pathway PI3K and PTEN, and their downstream pathways through ZEB1, ZEB2, HIF1A, VHL, CASP3 and PARP1 relating to prognosis in canine mammary cancer. For protein studies, the samples came from 58 female dogs with mammary neoplasia, immunohistochemistry was performed and its analysis by the histoscore method. For the genetic evaluation, the samples came from 13 patients, the DNA was extracted and the analysis for quantitative expression. Through immunohistochemistry, PI3K positivity was significantly associated with affected regional lymph node, distant metastasis, patients with HER2+, Triple Negative and Luminal B phenotypes, and the lowest survival rates. Through gene expression, we observed higher gene expression of ZEB2 and PARP1 both among patients who were alive and who died, which was not true for the expressions of PIK3CA and HIF1A. In conclusion, the data observed in this work are promising in the study of new molecular prognostic markers such as PI3K, ZEB2 and PARP1 for canine mammary cancer.

Mast Cell Tumour and Mammary Gland Carcinoma Collision Tumour. Case report and literature review.

Collision tumours are the coexistence, at the same venue, of distinct tumours not macroscopically distinguishable and consisting of two independent cell populations without histological admixture. In human medicine, collision tumours in different anatomical sites have been described. In the veterinary literature, few cases exist so far. A 12-year-old female Labrador with a mammary gland nodular lesion was presented for clinical examination. The nodule was surgically removed and underwent histological and immunohistochemical analysis. Histopathological examination revealed two distinct malignant tumours: a mammary gland carcinoma and a cutaneous mast cells tumour. To the author's knowledge, the paper reports the first case of a collision tumour composed of mammary gland neoplasia and mast cell tumour. The rising interest in collision tumours suggests widening their knowledge and setting up a multimodal approach that includes surgery and targeted therapy.

Escape from breast tumor dormancy: The convergence of obesity and menopause

Obesity is associated with an increased risk of, and a poor prognosis for, postmenopausal (PM) breast cancer (BC). Our goal was to determine whether diet-induced obesity (DIO) promotes 1) shorter tumor latency, 2) an escape from tumor dormancy, and 3) an acceleration of tumor growth and to elucidate the underlying mechanism(s). We have developed invitro assays and PM breast tumor models complemented by a noninvasive imaging system to detect vascular invasion of dormant tumors and have used them to determine whether obesity promotes the escape from breast tumor dormancy and tumor growth by facilitating the switch to the vascular phenotype (SVP) in PM BC. Obese mice had significantly higher tumor frequency, higher tumor volume, and lower overall survival compared with lean mice. We demonstrate that DIO exacerbates mammary gland hyperplasia and neoplasia, reduces tumor latency, and increases tumor frequency via an earlier acquisition of the SVP. DIO establishes a local and systemic proangiogenic and inflammatory environment via the up-regulation of lipocalin-2 (LCN2), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) that may promote the escape from tumor dormancy and tumor progression. In addition, we show that targeting neovascularization via a multitargeted receptor tyrosine kinase inhibitor, sunitinib, can delay the acquisition of the SVP, thereby prolonging tumor latency, reducing tumor frequency, and increasing tumor-free survival, suggesting that targeting neovascularization may be a potential therapeutic strategy in obesity-associated PM BC progression. This study establishes the link between obesity and PM BC and, for the first time to our knowledge, bridges the dysfunctional neovascularization of obesity with the earliest stages of tumor development.

Decoding the Therapeutic Implications of the ERα Stability and Subcellular Distribution in Breast Cancer.

Approximately 70% of all breast cancer cases are estrogen receptor-alpha positive (ERα+) and any ERα signaling pathways deregulation is critical for the progression of malignant mammary neoplasia. ERα acts as a transcription factor that promotes the expression of estrogen target genes associated with pro-tumor activity in breast cancer cells. Furthermore, ERα is also part of extranuclear signaling pathways related to endocrine resistance. The regulation of ERα subcellular distribution and protein stability is critical to regulate its functions and, consequently, influence the response to endocrine therapies and progression of this pathology. This minireview highlights studies that have deciphered the molecular mechanisms implicated in controlling ERα stability and nucleo-cytoplasmic transport. These mechanisms offer information about novel biomarkers, therapeutic targets, and promising strategies for breast cancer treatment.

Preneoplastic Low-Risk Mammary Ductal Lesions (Atypical Ductal Hyperplasia and Ductal Carcinoma In Situ Spectrum): Current Status and Future Directions.

Simple SummaryOvertreatment which means providing a patient with unnecessary medical intervention has recently become the center of attention in breast diseases. One of these lesions is low-risk ductal carcinoma in situ (DCIS), for which the standard of treatment is wide local excision/mastectomy, with or without radiation therapy, with or without hormonal therapy. There are many worldwide ongoing clinical trials aiming to de-escalate this therapy by examining whether active surveillance (AS) is sufficient. These trials vary in pathology inclusion and exclusion criteria. There is lack of consensus on the definition of low-risk DCIS, in particular the overlap with atypical ductal hyperplasia (ADH), DCIS grading, and lack of definition of comedonecrosis. This review discusses AS trial from pathology standpoint and provides few recommendations.Intraepithelial mammary ductal neoplasia is a spectrum of disease that varies from atypical ductal hyperplasia (ADH), low-grade (LG), intermediate-grade (IG), to high-grade (HG) ductal carcinoma in situ (DCIS). While ADH has the lowest prognostic significance, HG-DCIS carries the highest risk. Due to widely used screening mammography, the number of intraepithelial mammary ductal neoplastic lesions has increased. The consequence of this practice is the increase in the number of patients who are overdiagnosed and, therefore, overtreated. The active surveillance (AS) trials are initiated to separate lesions that require active treatment from those that can be safely monitored and only be treated when they develop a change in the clinical/radiologic characteristics. At the same time, the natural history of these lesions can be evaluated. This review aims to evaluate ADH/DCIS as a spectrum of intraductal neoplastic disease (risk and histomorphology); examine the controversies of distinguishing ADH vs. DCIS and the grading of DCIS; review the upgrading for both ADH and DCIS with emphasis on the variation of methods of detection and the definitions of upgrading; and evaluate the impact of all these variables on the AS trials.

Clinical, epidemiological, and histopathological aspects of breast cancer in female dogs at Federal Rural University of Rio de Janeiro Veterinary Hospital.

This study aimed to evaluate the clinical, epidemiological, and histopathological aspects of canine breast tumors at the Federal Rural University of Rio de Janeiro Veterinary Hospital (VH-UFRRJ) between April 2017 and October 2018. The study included 137 female canine dogs with mammary neoplasia who underwent a mastectomy. The animals were evaluated using a standard form that guided anamnesis and physical examination to assess the tumor’s epidemiology, development, evolution, treatment choice, and disease prognosis. Furthermore, laboratory and imaging tests were performed on the animals to search for changes that suggested metastasis. The average age of the female dogs was 10 years, and mixed-breed dogs (33%) were the most affected, followed by poodles (21%). The inguinal (79%) and caudal abdominal (64%) breasts were the most affected. Approximately 26% of the animals were castrated, 32% had already reproduced throughout their lives, 30% had pseudocyesis, and only 8% used contraceptive methods. The majority were classified as stage I (33%) and stage III (39%) according to the Tumor-Node-Metastasis (TNM) Classification System of Malignant Tumors. In 95 female dogs, 191 nodules were histopathologically evaluated, and 62% of these animals had at least one malignant tumor. Statistically, there was a direct association between tumor size and malignancy. However, other associations, such as age at diagnosis and the degree of malignancy, were not confirmed. Therefore, it can be concluded that tumor size is an important prognostic factor, with tumors >3 cm having an approximately 70% chance of being malignant.

Association of A4304G in exon eleven of Brca2 gene with canine mammary tumour

Canine mammary tumour is one among the prevalent life style diseases affecting dogs. Certain breeds of dogs are predisposed to mammary neoplasia indicating a possible role of genetic factors in the incidence of disease. Several candidate genes have been studied for its association with mammary tumour in dogs, of which Breast Cancer 2 is one among the genes responsible for the mammary tumour in dogs. In the current study, A4304G within exon 11 of Breast Cancer 2 gene was evaluated for its association with canine mammary tumour. The whole genomic DNA was extracted from 100 female dogs (50 mammary tumour affected dogs and 50 normal animals) above five years. Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) confirmed the presence of the concerned polymorphism among the 100 female dogs under study. On statistical analysis a significant association of the missense variant A4304G with mammary tumour could not be obtained.

533 Uncommon ECG presentation in Tako-tsubo syndrome

Abstract Aims We present the case of an 80-year-old woman without prior cardiovascular history, recent instrumental diagnosis of peritoneal carcinomatosis and ongoing oncologic diagnostic work up. Methods and results The patient was admitted to our ED for acute-onset worsening dyspnoea. On first clinical evaluation, she denied typical angina, remarkable clinical features were dyspnoea, tachycardia and hypotension. Admission ECG showed sinus rhythm with posterior and inferior ST elevation (leads DII, aVF, V5, V6) with reciprocal ST segment depression in leads V1–V2. Echocardiography confirmed infero-postero-lateral akinesia determining moderate reduction of LVEF (35–40%), normal aortic root, no pericardial effusion. Laboratory tests revealed normal WBC count, mild anaemia (HB 10.7 g/dl), normal renal function, elevated C-reactive protein (139 mg/l, n.v. < 8). Cardiac troponin I (cTnI) was normal on admission, with significant delta on second determination (0.012 > 2.5 ng/ml, nv < 0.023). ST elevation persisted after BP normalization and hypoxia treatment; so, taken into account the increased procedural risk due to patient’s age and comorbidities, however we decided to perform urgent coronary angiography. Surprisingly, coronary angiography revealed absence of any significant stenosis, with TIMI 3 flow in any coronary segment. The patient was then admitted to the ICU with diagnosis of MINOCA. The next day ECG revealed normalization of ST segment and Q wave in V2–V3. On day 2 new ECG showed new ventricular repolarization abnormalities with T wave inversion in precordial leads. Peak hs-cTnI was >15 000 ng/l. Repeat echocardiography on day 2 reported complete akinesia of all the apical segments of the LV with normo-hyperkinesia of the mid-basal segments (apical ballooning pattern) and severely depressed systolic function (FE 32–35%). During the following days patient’s symptoms improved, with rapid weaning from oxygen therapy and stable haemodynamic parameters. After 10 days the patient repeated echocardiography, which revealed improvement of global LVEF and persisting mild apical hypokinesia, suggesting the diagnostic hypothesis of Tako-Tsubo Syndrome (TTS) or TTS-phenocopy (unfortunately cardiac MRI was not performed). The patient was therefore transferred to oncology department to complete the diagnostic work-up; primary mammary neoplasia was identified, moreover associated with metastasis in the liver and the brain. Unfortunately, the patient died a month later due to non-cardiac causes. This is the case report of an uncommon MINOCA, which presented mimicking inferolateral acute STEMI, but subsequent ECG and echocardiographic evolution showed the more typical TTS pattern, with apical ballooning on echo and deep negative T waves in anterior leads. Conclusions The prevalence of MINOCA is estimated to be 6% to 8% among patients diagnosed with MI, especially women, however it is more common in patients with NSTEMI compared with STEMI; moreover in cases of TTS presenting with ST elevation, usually the elevation is found in anterior leads without reciprocal ST depression; in this patient instead ST elevation was inferolateral with reciprocal anterior ST depression. Absence of obstructive CAD and clinical/echocardiographic evolution allowed us to confirm the diagnosis of MINOCA/TTS.

Milk fat as a source of bioactive compounds

Milk fat as a source of bioactive compounds

Repurposing Combination Therapy of Voacamine With Vincristine for Downregulation of Hypoxia-Inducible Factor-1α/Fatty Acid Synthase Co-axis and Prolyl Hydroxylase-2 Activation in ER+ Mammary Neoplasia.

The current study investigated the role of combination therapy with voacamine and vincristine in preventing mammary gland carcinoma through prolyl hydroxylase-2 activation. Prolyl hydroxylase-2 activation leads to the downregulation of hypoxia-inducible factor-1α and fatty acid synthase. Overexpression of hypoxia-inducible factor-1α and fatty acid synthase has been previously reported in solid tumors of the mammary gland. After screening a battery of natural compounds similar to vincristine, voacamine was selected as a possible prolyl hydroxylase-2 activator, and its activity was evaluated using a 7,12-dimethylbenz[a]anthracene-induced rat model. The combination therapy was evaluated for cardiac toxicity using a hemodynamic profile. Angiogenic markers were evaluated by carmine staining. Monotherapy and combination therapy were also evaluated for liver and kidney toxicity using hematoxylin and eosin staining. The antioxidant potential was delineated using oxidative stress markers. The serum metabolomic profile was studied using NMR spectroscopy, and the disruption of fatty acids was evaluated using gas chromatography. Western blotting of proteins involved in hypoxic pathways was performed to decipher the action of therapy at the molecular level. Immunoblotting analysis validated that combination therapy has potential toss with prolyl hydroxylase-2 activity and thus initiates proteolytic degradation of hypoxia-inducible factor-1α and its consequent effects. Combination therapy also stimulated programmed cell death (apoptosis) in rapidly dividing cancer cells. The present study explored the role of voacamine inactivation of prolyl hydroxylase-2, which can decrease the overexpression of hypoxia-inducible factor-1α and fatty acid synthase in mammary gland carcinoma cells.

"Borderline" epithelial lesions of the breast: what have we learned in the past three decades?

SummaryAtypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH) and flat epithelial atypia (FEA) are common lesions mainly detected during mammographic screening. They are considered lesions at risk for the development of breast cancer, and they have been documented as non-obligate precursors of low grade in situ carcinomas. In a monumental work in 1991 Rosai gathered them as “borderline epithelial lesions”, and he described and demonstrated the subjectivity in their microscopic interpretation. Such subjectivity persists nowadays and limits considerably the diagnostic consistency. With his incredible ability to see, analyze and rationalize, Rosai introduced the concept of “mammary intraepithelial neoplasia (MIN) of either ductal or lobular type, followed by a grading system” which would have better represented the biological continuum between these lesions and benign and malignant lesions.

Reduced menin expression leads to decreased ER\u03b1 expression and is correlated with the occurrence of human luminal B-like and ER-negative breast cancer subtypes

PurposeMenin, encoded by the MEN1 gene, was recently reported to be involved in breast cancers, though the underlying mechanisms remain elusive. In the current study, we sought to further determine its role in mammary cells.MethodsMenin expression in mammary lesions from mammary-specific Men1 mutant mice was detected using immunofluorescence staining. RT-qPCR and western blot were performed to determine the role of menin in ERα expression in human breast cancer cell lines. ChIP-qPCR and reporter gene assays were carried out to dissect the action of menin on the proximal ESR1 promoter. Menin expression in female patients with breast cancer was analyzed and its correlation with breast cancer subtypes was investigated.ResultsImmunofluorescence staining revealed that early mammary neoplasia in Men1 mutant mice displayed weak ERα expression. Furthermore, MEN1 silencing led to both reduced ESR1 mRNA and ERα protein expression in MCF7 and T47D cells. To further dissect the regulation of ESR1 transcription by menin, we examined whether and in which way menin could regulate the proximal ESR1 promoter, which has not been fully explored. Using ChIP analysis and reporter gene assays covering − 2500 bp to + 2000 bp of the TSS position, we showed that the activity of the proximal ESR1 promoter was markedly reduced upon menin downregulation independently of H3K4me3 status. Importantly, by analyzing the expression of menin in 354 human breast cancers, we found that a lower expression was associated with ER-negative breast cancer (P = 0.041). Moreover, among the 294 ER-positive breast cancer samples, reduced menin expression was not only associated with larger tumors (P = 0.01) and higher SBR grades (P = 0.005) but also with the luminal B-like breast cancer subtype (P = 0.006). Consistent with our clinical data, we demonstrated that GATA3 and FOXA1, co-factors in ESR1 regulation, interact physically with menin in MCF7 cells, and MEN1 knockdown led to altered protein expression of GATA3, the latter being a known marker of the luminal A subtype, in MCF7 cells.ConclusionTaken together, our data provide clues to the important role of menin in ERα regulation and the formation of breast cancer subtypes.