Mammary Tumor Research Articles

HN1 expression contributes to mitotic fidelity through Aurora A-PLK1-Eg5 axis.

Hematological and neurological expressed 1 (HN1) is homolog of Jupiter protein from Drosophila melanogaster where it functions as a microtubule-associated protein. However, in mammalian cells, HN1 is associated partially with y-tubulin in centrosomes, Stathmin for stabilizing microtubules, and Cdh1 for regulating Cyclin B1 for cell cycle regulation. Moreover, HN1 overexpression leads to early mitotic exit as well. Other molecular functions and interactions of HN1 are not clear yet. Here, based on our previous analysis where HN1 was shown to cluster supernumerary centrosomes and maintain mitotic spindle assembly, we further investigated the role of HN1 in centrosome maintenance and mitotic fidelity in PC-3 prostate and MDA-MB231 mammary cancer cell lines. The maturation-associated roles of HN1 during cell division by examining the AuroraA-PLK1 axis involving a plus end kinesin, Eg5 as well as pericentriolar matrix protein (PCM1) as components of centrosomes were established. We found that HN1 co-localized to centrioles with Eg5 and Aurora A to suppress aberrant spindle formation to ensure the fidelity of centriole/centrosome duplication when overexpressed. Consistently, depleting the HN1 expression using siRNA or shRNA resulted in an increased number of dysregulated mitotic spindle structures, where Aurora A as well as PLK1 co-localizations with Eg5 and PCM1 were disrupted. Further, the PLK1 and Aurora A kinase's phosphorylations also decreased, confirming the hypothesis that the cells struggle in mitotic progression, display nuclear and cytokinetic abnormalities with supernumerary but immature mononucleated centrosomes. In summary, we described the role of HN1 in centrosome nucleation/maturation in PLK1-Eg5 axis and concomitant mitotic spindle formation in human cells.

Abstract A080: An analysis of outcomes in patients (pts) with advanced pancreatic cancer (PDAC) whose tumors harbor pathogenic BRCA1 or BRCA2 mutations based on gene mutation location

Abstract Introduction: BRCA1/2 mutations in pts with PDAC predict for an improved tumor response, higher median time to progression (TTP), and longer median overall survival (mOS) with platinum-based therapy (tx) as compared to non-platinum-based tx. We examined whether mutations within specific regions of the BRCA1/2 genes correlate to any differences in mTTP or mOS in this pt population. Methods: An established database of PDAC pts seen at Johns Hopkins University from 2018 to 2023, whose tumors underwent next-generation DNA sequencing was queried for the presence of a path/likely path BRCA1/2 mutation. The pathogenicity of each BRCA1/2 mutation was confirmed using the NCI Clinvar database. Pt disease characteristics and tx information was captured from the electronic medical record. OS was defined from the time of diagnosis of advanced/metastatic disease until death. First line platinum-treated mTTP was defined from tx initiation until disease progression. Results: We identified 258 pts with BRCA1/2 mutations, 56 with path/likely mutations, of which 41% were male, 80% were Caucasian and 10% African American, with a median age at diagnosis of 66 (range 42-85). Consistent with our previously published data, the mOS for pts with BRCA1/2 mutations was greater with platinum tx at any time during their PDAC survival compared to never having any platinum tx (BRCA 1: 20.5 months vs 10.2 months n=16; BRCA 2: 15.7 months vs 5 months n=40). mTTP and mOS were analyzed based on where along the gene the BRCA mutations occurred. For BRCA1, mutations clustered in 3 groups (G1 BARD1-binding; G2 Exon11/Check2 binding; and G3 BRCT region). For BRCA2, mutations clustered in 3 groups (G1 N-terminal; G2 BRC repeats/RAD51 binding; and G3 DNA Binding). For pts with BRCA1 mutations, pts in Group 2 had the worst mOS and mTTP. For example, mOS (months) was: G1=39.9, G2=13.3; G3=26.5. For pts with BRCA2 mutations, pts in Group 2 had the worst mOS (months): G1=34.1, G2=14.9; G3= 20.2. However, for BRCA2, there were no differences in mTTP. Conclusions: Evaluation of survival in pts with BRCA1/2 mutated PDAC reveals differences in mOS and mTTP as a function of the location of the mutation along the gene. In particular, pts with BRCA 1 exon 11 mutations had the worst mOS, consistent with previous in vivo studies in which Brca1Δ11/Δ11 mouse mammary tumors were resistant to cisplatin. By contrast, mutations in the C-terminal DNA binding domain of BRCA2 had better mOS, also consistent with previous studies. Interestingly, we did not observe prolonged survival in pts with BRCA2 exon 11 mutations, as has been observed in ovarian cancer, likely reflecting a difference in platinum sensitivity between the two diseases. Further evaluation of the relevance of the specific mutation location as it relates to interaction with other elements of the homologous recombination repair machinery, other genetic lesions, and the tumor microenvironment, are warranted to help understand what specifically mediates sensitivity to platinums in a BRCA1/2-mutated PDAC. Citation Format: Jamie Hur, Thomas McPhaul, Dea Cunningham, Lei Zheng, Christopher J Pishvaian, Daniel Laheru, Ana De Jesus-Acosta, Dung Le, Neeha Zaidi, Nilo Azad, Ilene Browner, William R Burns, Richard Burkhart, Kelly Lafaro, Amol Narang, Jin He, Valerie Lee, Jonathan R Brody, Michael J Pishvaian. An analysis of outcomes in patients (pts) with advanced pancreatic cancer (PDAC) whose tumors harbor pathogenic BRCA1 or BRCA2 mutations based on gene mutation location [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A080.

A brain-body feedback loop driving HPA-axis dysfunction in breast cancer.

Breast cancer patients often exhibit disrupted circadian rhythms in circulating glucocorticoids (GCs), such as cortisol. This disruption correlates with reduced quality of life and higher cancer mortality 1-3 . The exact cause of this phenomenon - whether due to treatments, stress, age, co-morbidities, lifestyle factors, or the cancer itself remains unclear. Here, we demonstrate that primary breast cancer alone blunts host GC rhythms by disinhibiting neurons in the hypothalamus, and that circadian phase-specific neuromodulation of these neurons can attenuate tumor growth by enhancing anti-tumor immunity. We find that mice with mammary tumors exhibit blunted GC rhythms before tumors are palpable, alongside increased activity in paraventricular hypothalamic neurons expressing corticotropin-releasing hormone (i.e., PVN CRH neurons). Tumor-bearing mice have fewer inhibitory synapses contacting PVN CRH neurons and reduced miniature inhibitory post-synaptic current (mIPSC) frequency, leading to net excitation. Tumor-bearing mice experience impaired negative feedback on GC production, but adrenal and pituitary gland functions are largely unaffected, indicating that alterations in PVN CRH neuronal activity are likely a primary cause of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in breast cancer. Using chemogenetics (hM3Dq) to stimulate PVN CRH neurons at different circadian phases, we show that stimulation just before the light-to-dark transition restores normal GC rhythms and reduces tumor progression. These mice have significantly more effector T cells (CD8+) within the tumor than non-stimulated controls, and the anti-tumor effect of PVN CRH neuronal stimulation is absent in mice lacking CD8+ T cells. Our findings demonstrate that breast cancer distally regulates neurons in the hypothalamus that control output of the HPA axis and provide evidence that therapeutic targeting of these neurons could mitigate tumor progression.

Mcam stabilizes a luminal progenitor-like breast cancer cell state via Ck2 control and Src/Akt/Stat3 attenuation

Cell state control is crucial for normal tissue development and cancer cell mimicry of stem/progenitor states, contributing to tumor heterogeneity, therapy resistance, and progression. Here, we demonstrate that the cell surface glycoprotein Mcam maintains the tumorigenic luminal progenitor (LP)-like epithelial cell state, leading to Basal-like mammary cancers. In the Py230 mouse mammary carcinoma model, Mcam knockdown (KD) destabilized the LP state by deregulating the Ck2/Stat3 axis, causing a switch to alveolar and basal states, loss of an estrogen-sensing subpopulation, and resistance to tamoxifen—an effect reversed by Ck2 and Stat3 inhibitors. In vivo, Mcam KD blocked generation of Basal-like tumors and Sox10+Krt14+ cells. In human tumors, MCAM loss was largely exclusive of the Basal-like subtype, linked instead to proliferative Luminal subtypes, including often endocrine-resistant Luminal B cancers. This study has implications for developing therapies targeting MCAM, CK2, and STAT3 and their likely effective contexts.

Impact of Toceranib Phosphate and Carprofen on Survival and Quality of Life in Dogs with Inflammatory Mammary Carcinomas.

Canine inflammatory mammary carcinoma (IMC) is an aggressive and rare type of mammary gland cancer in dogs where vascular endothelial growth factor and cyclooxigenase-2 overexpression usually occur, which contribute to its invasive and angiogenic nature. This study aimed to evaluate the efficacy and safety of a combined treatment regimen of toceranib phosphate and carprofen in dogs with measurable IMC. Fifteen female dogs with histopathologically confirmed IMC were included, undergoing a regimen of toceranib (2.4-2.75 mg/kg PO, three times weekly) and carprofen (4.4 mg/kg/24 h PO). Initial evaluations included physical exams, tumor measurements, complete blood count, biochemistry, urinalysis, three view thoracic radiographs, and abdominal ultrasound. Follow-up assessments of physical condition and quality of life (QOL) were conducted bi-weekly, with tumor response evaluations monthly, using RECIST v1.0 criteria. While no complete or partial responses were observed, 60% of the dogs maintained stable disease, with a median progression-free survival of 76 days and an overall survival of 90 days. Notably, 60% of the dogs showed clinical benefit through improved QOL and disease stabilization. The treatment was well-tolerated, with only grade I/II toxicities reported. Despite limited biological activity against the cancer, this protocol may enhance QOL in dogs with IMC, offering a valuable palliative option.

ERK1/2 mitogen-activated protein kinase dimerization is essential for the regulation of cell motility.

ERK1/2 mitogen-activated protein kinases (ERK) are key regulators of basic cellular processes, including proliferation, survival, and migration. Upon phosphorylation, ERK becomes activated and a portion of it dimerizes. The importance of ERK activation in specific cellular events is generally well documented, but the role played by dimerization is largely unknown. Here, we demonstrate that impeding ERK dimerization precludes cellular movement by interfering with the molecular machinery that executes the rearrangements of the actin cytoskeleton. We also show that a constitutively dimeric ERK mutant can drive cell motility per se, demonstrating that ERK dimerization is both necessary and sufficient for inducing cellular migration. Importantly, we unveil that the scaffold protein kinase suppressor of Ras 1 (KSR1) is a critical element for endowing external agonists, acting through tyrosine kinase receptors, with the capacity to induce ERK dimerization and, subsequently, to unleash cellular motion. In agreement, clinical data disclose that high KSR1 expression levels correlate with greater metastatic potential and adverse evolution of mammary tumors. Overall, our results portray both ERK dimerization and KSR1 as essential factors for the regulation of cell motility and mammary tumor dissemination.

USP11 deubiquitinates E-cadherin and maintains the luminal fate of mammary tumor cells to suppress breast cancer

Basal-like breast cancer may originate from luminal epithelial or cancerous cells. Inadequately repaired DNA damage impairs luminal differentiation and promotes aberrant luminal to basal trans-differentiation in mammary epithelial cells (MECs). Ubiquitin-specific peptidase 11 (USP11), a deubiquitinase, plays a critical role in DNA damage repair. The role of USP11 in controlling mammary cell differentiation and tumorigenesis remains poorly understood. We generated Usp11 knockout mice and breast cancer cell lines expressing wild-type (WT) and mutant form of USP11. By using these mutant mice, cell lines, and human USP11-deficient and -proficient breast cancer tissues, we tested how USP11 controls mammary cell fate. We generated Usp11 knock-out mice and found that deletion of Usp11 reduced the expression of E-cadherin and promoted DNA damage in MECs. Overexpression of WT USP11, but not a deubiquitinase-inactive mutant form of USP11, promoted luminal differentiation, enhanced DNA damage repair, and suppressed tumorigenesis in mice. Mechanistically, we found that USP11 enhanced the protein expression of E-cadherin dependent on its deubiquitinase activity, and that USP11 deubiquitinated E-cadherin at K738. We discovered that USP11 bound to E-cadherin through its C-terminal region. In human breast cancers, expression of USP11 was positively correlated with that of E-cadherin, and high USP11 predicted better recurrence-free survival. Our findings provide compelling genetic and biochemical evidence that USP11 not only promotes DNA damage repair but also deubiquitinates E-cadherin and maintains the luminal feature of mammary tumor cells, thereby suppressing luminal breast cancer.

Microwave synthesis, density functional theory study and antiproliferative activity of the novel spiropyrazole derivatives

Different spiro-pyrazole-oxy-indoline substituted compounds I-IV have been synthesized. In Jaguar, Hybrid DFT using Becke’s three-parameter transfer possibility also,Lee-Yang-Parr correlated practical (B3LYP) viewwith a 6-31 G** basis set were utilized to improve the geometrical characteristics of the hit molecules and reference compound. The MTT test exhibited whether the prepared substance has an inhibitory impact on cell development or not. This was successfully represented that in hepatocellular carcinoma (HEPG-2), colorectal carcinoma (HCT-116), and mammary gland breast cancer cell lines (MCF-7) colorimetric test, the mitochondrial succinate dehydrogenase in live cells transform yellow tetrazolium bromide (MTT) to a purple formazan product. Compound IV was found to be a better cytotoxic action against to the HEPG-2 hepatocellular carcinoma cell line, and it has been seen a strong activity against the colorectal carcinoma cell lines HCT-116 and MCF-7 mammary gland breast cancer cell lines. While the other three compounds I, II, and III showed a moderate cytotoxic action to high action against the same cell lines.

Integrated Study of Canine Mammary Tumors Histopathology, Immunohistochemistry, and Cytogenetic Findings.

Cancer is a complex pathological condition associated with substantial rates of mortality and morbidity in both humans and animals. Mammary gland tumors in intact female dogs are the most prevalent neoplasms. Surgical intervention remains the primary treatment choice. Alternative therapeutic options have emerged, with histopathological examination being fundamental to confirm the diagnosis and to decide the best therapy. This research focused on the clinicopathological, immunohistochemical, and cytogenetic aspects of canine mammary tumors (CMTs). Most of the animals were mixed-breed, with the majority being older than seven years, and only 16.7% had been spayed before surgery. Caudal abdominal and inguinal mammary glands were the most affected, with regional mastectomy being the predominant treatment (75.0%). Of all the tumors, 29.1% were benign, while 70.9% were malignant. Complex adenoma was the most common benign tumor, whereas tubulopapillary carcinoma was the most common malignant type. Grade III tumors (17.6%) were the least encountered, while grades I and II exhibited a similar prevalence (41.2%). All the carcinomas were classified as luminal, and cytogenetics analysis demonstrated a high chromosomal instability with significant aneuploidy observed in all cases and polyploidy detected in 62.5%. This study holds significance as canine and human breast cancers share similar characteristics, suggesting that dogs could be a valuable model for human breast cancer research. Further studies with larger sample sizes are needed to enhance our understanding of CMTs.

Dihydroxyphenylalanine-conjugated high molecular weight polyethylenimine for targeted delivery of Plasmid

High molecular weight polyethylenimine (HMW PEI; branched 25 kDa PEI) has been widely investigated for gene delivery due to its high transfection efficiency. However, the toxicity and lack of targeting to specific cells have limited its clinical application. In the present investigation, L-3, 4‐dihydroxyphenylalanine (L-DOPA) was conjugated on HMW PEI in order to target L-type amino acid transporter 1 (LAT-1) and modulate positive charge density on the surface of polymer/plasmid complexes (polyplexes). The results of biophysical characterization revealed that the PEI conjugates are able to form nanoparticles ≤ 180 nm with the zeta potential ranging from + 9.5–12.4 mV. These polyplexes could condense plasmid DNA and protect it against nuclease digestion at the carrier to plasmid ratios higher than 4. L-DOPA conjugated PEI derivatives were complexed with a plasmid encoding human interleukin-12 (hIL-12). Targeted polyplexes showed up to 2.5 fold higher transfection efficiency in 4T1 murine mammary cancer cell line, which expresses LAT-1, than 25 kDa PEI polyplexes prepared in the same manner. The cytotoxicity of these polyplexes was also substantially lower than the unmodified parent HMW PEI. These results support the use of L-3, 4‐dihydroxyphenylalanine derivatives of PEI in any attempt to develop a LAT-1 targeted gene carrier.

An Abscopal Effect on Lung Metastases in Canine Mammary Cancer Patients Induced by Neoadjuvant Intratumoral Immunotherapy with Cowpea Mosaic Virus Nanoparticles and Anti-Canine PD-1.

Neoadjuvant intratumoral (IT) therapy could amplify the weak responses to checkpoint blockade therapy observed in breast cancer (BC). In this study, we administered neoadjuvant IT anti-canine PD-1 therapy (IT acPD-1) alone or combined with IT cowpea mosaic virus therapy (IT CPMV/acPD-1) to companion dogs diagnosed with canine mammary cancer (CMC), a spontaneous tumor resembling human BC. CMC patients treated weekly with acPD-1 (n = 3) or CPMV/acPD-1 (n = 3) for four weeks or with CPMV/acPD-1 (n = 3 patients not candidates for surgery) for up to 11 weeks did not experience immune-related adverse events. We found that acPD-1 and CPMV/acPD-1 injections resulted in tumor control and a reduction in injected tumors in all patients and in noninjected tumors located in the ipsilateral and contralateral mammary chains of treated dogs. In two metastatic CMC patients, CPMV/acPD-1 treatments resulted in the control and reduction of established lung metastases. CPMV/acPD-1 treatments were associated with altered gene expression related to TLR1-4 signaling and complement pathways. These novel therapies could be effective for CMC patients. Owing to the extensive similarities between CMC and human BC, IT CPMV combined with approved anti-PD-1 therapies could be a novel and effective immunotherapy to treat local BC and suppress metastatic BC.

Auranofin Suppresses the Growth of Canine MammaryTumour Cells and Induces Apoptosis via thePI3K/AKT Pathway.

Canine mammary gland tumour (CMT) is the most common spontaneous tumour in intact female dogs and often exhibits metastases. Auranofin (AF) is a gold complex used for treating rheumatism. The excellent anti-tumour ability of AF has been demonstrated in various types of human and canine tumours. In this study, five CMT cell lines (CIPp, CMT-7364, CHMp, CIPm and CTBp) and three CMT primary cells (G7894, L1883 and L6783) were used to explore the anti-tumour effect of AF on CMT. Two CMT cell lines (CIPp and CMT-7364) were used to search the underlying mechanism of the effect of AF on CMT. The results showed that AF inhibited the growth, migration, invasion, and colony formation abilities of CMT cells. Additionally, the growth of CMT in a 3D cell culture model was effectively suppressed by AF. Furthermore, AF induced cell apoptosis of CMT cells via the PI3K/AKT pathway. In conclusion, AF effectively induces CMT apoptosis by regulating the PI3K/AKT pathway, indicating that AF should be explored as a potential CMT treatment in future studies.

Hybrid embedded and filter feature selection methods in big-dimension mammary cancer and prostatic cancer data

<p>The feature selection method enhances machine learning performance by enhancing learning precision. Determining the optimal feature selection method for a given machine learning task involving big-dimension data is crucial. Therefore, the purpose of this study is to make a comparison of feature selection methods highlighting several filters (information gain, chi-square, ReliefF) and embedded (Lasso, Ridge) hybrid with logistic regression (LR). A sample size of n=100, 75 is chosen randomly, and the reduction features d=50, 22, and 10 are applied. The procedure for feature reduction makes use of the entire sample sizes. Each sample size's results are compared, including tests with no feature selection process. The results indicate that LR+ReliefF is the best method for mammary cancer data, whereas LR+IG is the best for prostatic cancer data, making the filter more suitable than embedded for big-dimension data. This study revealed that the sample's features and size influence the most effective method for selecting features from big-dimension data. Therefore, it provides insight into the most effective methods for particular features and sample sizes in high-dimensional data.</p>

The association between infectious agents and breast cancer: a review of the epidemiologic evidence.

Several viruses have been casually linked to human cancers, including cervical, nasopharyngeal, liver, sarcoma, and Merkel cell carcinomas. However, the etiologic contribution of viral infections to breast cancer, the number one incident cancer among women worldwide, is not well established. Among studies exploring associations of viruses with breast cancer, potential linkages have been identified between breast cancer and five viruses: beta retrovirus, (i.e., mouse mammary tumor virus), human papillomavirus, Epstein Barr virus. bovine leukemia virus, and human cytomegalovirus. In this review, we provide a comprehensive evaluation of epidemiological ecologic, case-control, case-only, and cohort studies investigating these associations. Wediscuss results from several existing reviews and meta-analyses, evaluate epidemiological studies published in the past five years, and assess the relationship between these viruses and breast tumor clinicopathological factors. The strongest epidemiological evidence for a viral role in breast cancer exists for MMTV and HPV, though limitations include lack of prospective studies for MMTV and potential detection bias in HPV studies. Viral detection challenges have limited studies of EBV and HCMV. Fewer studies have evaluated BLV, and though it has been associated with higher risk of breast cancer, sample sizes are quite small. CONCLUSION: While epidemiologic evidence exists for an association between these five viruses and breast cancer, various methodological issues and lack of prospective studies preclude robustconclusions. Future research should prioritize establishing a temporal relationship between infection and disease, minimizing misclassification of detection assays, and further exploring the influence of co-infections.

A novel lipophilic amiloride derivative efficiently kills chemoresistant breast cancer cells

Derivatives of the potassium-sparing diuretic amiloride are preferentially cytotoxic toward tumor cells relative to normal cells, and have the capacity to target tumor cell populations resistant to currently employed therapeutic agents. However, a major barrier to clinical translation of the amilorides is their modest cytotoxic potency, with estimated IC50 values in the high micromolar range. Here we report the synthesis of ten novel amiloride derivatives and the characterization of their cytotoxic potency toward MCF7 (ER/PR-positive), SKBR3 (HER2-positive) and MDA-MB-231 (triple negative) cell line models of breast cancer. Comparisons of derivative structure with cytotoxic potency toward these cell lines underscore the importance of an intact guanidine group, and uncover a strong link between drug-induced cytotoxicity and drug lipophilicity. We demonstrate that our most potent derivative called LLC1 is preferentially cytotoxic toward mouse mammary tumor over normal epithelial organoids, acts in the single digit micromolar range on breast cancer cell line models representing all major subtypes, acts on cell lines that exhibit both transient and sustained resistance to chemotherapeutic agents, but exhibits limited anti-tumor effects in a mouse model of metastatic breast cancer. Nonetheless, our observations offer a roadmap for the future optimization of amiloride-based compounds with preferential cytotoxicity toward breast tumor cells.

Depth for samples of sets with applications to testing equality in distribution of two samples of random sets

This paper introduces several depths for random sets with possibly non-convex realisations, proposes ways to estimate the depths based on the samples and compares them with existing ones. The depths are further applied for the comparison between two samples of random sets using a visual method of DD-plots and statistical testing. The advantage of this approach is identifying sets within the sample that are responsible for rejecting the null hypothesis of equality in distribution and providing clues on differences between distributions. The method is justified using a simulation study and applied to real data consisting of histological images of mastopathy and mammary cancer tissue.

Comparative in vitro and in silico analysis of the ability of basic Asp49 phospholipase A2 and Lys49-phospholipase A2-like myotoxins from Bothrops diporus venom to inhibit the metastatic potential of murine mammary tumor cells and endothelial cell tubulogenesis: Asp49 vs Lys49 phospholipases A2: Inhibition of metastasis and angiogenesis

Snake venoms are a complex mixture of proteins and polypeptides that represent a valuable source of potential molecular tools for understanding physiological processes for the development of new drugs. In this study two major PLA2s, named PLA2-I (Asp49) and PLA2-II (Lys49), isolated from the venom of Bothrops diporus from Northeastern Argentina, have shown cytotoxic effects on LM3 murine mammary tumor cells, with PLA2-II-like exhibiting a stronger effect compared to PLA2-I. At sub-cytotoxic levels, both PLA2s inhibited adhesion, migration, and invasion of these adenocarcinoma cells. Moreover, these toxins hindered tubulogenesis in endothelial cells, implicating a potential role in inhibiting tumor angiogenesis. All these inhibitory effects were more pronounced for the catalytically-inactive toxin. Additionally, in silico studies strongly suggest that this PLA2-II-like myotoxin could effectively block fibronectin binding to the integrin receptor, offering a dual advantage over PLA2-I in interacting with the αVβ3 integrin. In conclusion, this study reports for the first time, integrating both in vitro and in silico approaches, a comparative analysis of the antimetastatic and antiangiogenic potential effects of two isoforms, an Asp49 PLA2-I and a Lys49 PLA2-II-like, both isolated from Bothrops diporus venom.

Promoting effect of sunset yellow on N-methyl N-nitrosourea-induced rat mammary carcinogenesis: Implications of molecular mechanisms

BackgroundNowadays, the use of food additives, such as Sunset Yellow (SY), is growing, which attracted attention to the potential relationship between some diseases and food additives. AimThe study aimed to investigate the role of Sunset Yellow during chemically-induced mammary gland carcinogenesis in Sprague–Dawley rats. Material and methodsThree groups of female rats were intraperitoneally administered with N-methyl-N-nitrosourea (MNU). Group 1 was set on a basal diet. Group 2 was treated with 161.4 mg\\kg\\day Sunset Yellow (SY). Group 3 was given SY at 80.7 mg\\kg\\day. Groups 4–6 were not administered MNU; Group 4 received vehicles only. Groups 5 and 6 were administered SY similarly to groups 2 and 3 respectively. ResultsSunset Yellow at both doses exerted a significant dose-dependent increase in tumor incidences, multiplicities, volumes, and decreased tumor latency as compared with control. Immunolabeling indexes of the proliferating cell nuclear antigen, estrogen receptor alpha, and progesterone receptor were significantly increased after SY treatment. Oxidative stress markers, serum estrogen, progesterone, and prolactin levels were significantly modified by SY treatment. The mRNA expression of estrogen receptor alpha and epidermal growth factor was up-regulated in SY groups versus control. ConclusionCollectively, SY has significantly promoted MNU-induced mammary tumors in rats with underlying mechanisms correlating SY consumption with estrogen disruption and subsequent antioxidative stress discrepancy.

Cytological Features of Inflammatory Mammary Carcinoma in Dogs.

Inflammatory mammary carcinoma (IMC) is the most aggressive and malignant type of mammary carcinoma. As in humans, canine IMC resembles mastitis clinically. However, IMC is highly aggressive with high incidence of metastases and common recurrence after surgery, leading to guarded prognosis and low survival rate. Given the complex morphology of canine mammary tumours, cytological examination is not performed routinely, and IMC diagnosis relies on the association of clinical features and histopathology. The purpose of this study is to describe the characteristics of canine IMC cytology, in an attempt to find possible cytological features that allow differentiation of IMC from other mammary tumour types. We analysed preoperative cytological samples from 25 dogs with IMC, later confirmed by corroborating clinical and histopathological examinations. Distinct cytological features of canine IMC included scarce cellular cohesiveness, ballooning aspect of neoplastic cells, frequent multinucleation, irregularly dispersed and ropy chromatin pattern, and squamous metaplasia in some individualised cells or those in small groups. Our results indicate that cytological examination can contribute to the diagnosis of IMC and might help differentiate it from other mammary carcinomas, even when clinical data is not available, which is common in cytological routine.

Prognostic Value of Fas/Fas Ligand Expression on Circulating Tumor Cells (CTCs) and Immune Cells in the Peripheral Blood of Patients with Metastatic Breast Cancer.

The Fas/Fas ligand (FasL) system is a major apoptosis-regulating pathway with a key role in tumor immune surveillance and metastasis. The expression of Fas/FasL on mammary tumor tissues holds prognostic value for breast cancer (BC) patients. We herein assessed Fas/FasL expression on circulating tumor cells (CTCs) and matched peripheral blood mononuclear cells (PBMCs) from 98 patients with metastatic BC receiving first-line treatment. Fas+, FasL+, and Fas+/FasL+ CTCs were identified in 88.5%, 92.3%, and 84.6% of CTC-positive patients, respectively. In addition, Fas+/FasL+, Fas-/FasL+, and Fas-/FasL- PBMCs were identified in 70.3%, 24.2%, and 5.5% of patients, respectively. A reduced progression-free survival (PFS) was revealed among CTC-positive patients (median PFS: 9.5 versus 13.4 months; p = 0.004), and specifically among those harboring Fas+/FasL+ CTCs (median PFS: 9.5 vs. 13.4 months; p = 0.009). On the other hand, an increased overall survival (OS) was demonstrated among patients with Fas+/FasL+ PBMCs rather than those with Fas-/FasL+ and Fas-/FasL- PBMCs (median OS: 35.7 vs. 25.9 vs. 14.4 months, respectively; p = 0.008). These data provide for the first time evidence on Fas/FasL expression on CTCs and PBMCs with significant prognostic value for patients with metastatic BC, thus highlighting the role of the Fas/FasL system in the peripheral immune response and metastatic progression of BC.