Hormone Receptor Expression Analyses in Neoplastic and Non-Neoplastic Canine Mammary Tissue by a Bead Based Multiplex Branched DNA Assay: A Gene Expression Study in Fresh Frozen and Formalin-Fixed, Paraffin-Embedded Samples

Mohr, Annika; Ripoli, Florenza Lüder; Hammer, Susanne Conradine; Willenbrock, Saskia; Hewicker‐Trautwein, M.; Kiełbowicz, Zdzisław; Escobar, Hugo Murua; Nolte, Ingo

doi:10.1371/journal.pone.0163311

Cited by 14 publications

(23 citation statements)

References 34 publications

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“…42 Our study, in turn, showed a significantly lower expression of the transcript in carcinomas than in adenomas and normal glands, a finding also described in the literature. 27 As expected, ESR1 transcript level corresponded to ERa protein expression. However, three of the six carcinomas that showed a score 0 for the ERa protein expressed ESR1 mRNA.…”

Section: Discussionsupporting

confidence: 70%

“…Similar data concerning ERa have been reported in human breast 15 and ovarian cancers. 19 This divergence among transcript and protein levels has been attributed to the variations in the immunohistochemical assay 17,27 techniques, such as antibody clones and fixation time of the tissue. 30 However, other factors such as posttranscriptional regulation should also be considered.…”

Section: Discussionmentioning

confidence: 99%

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DNA Methylation Status of the Estrogen Receptor α Gene in Canine Mammary Tumors

et al. 2018

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Estrogen receptor α (ERα) has an important role in mammary carcinogenesis, prognosis, and treatment. In human and canine mammary cancer, the most aggressive tumors show loss of ERα expression, which in human breast cancer has been attributed to methylation of the cytosine followed by guanine (CpG) island within the estrogen receptor α gene ( ESR1) promoter. This study aimed to investigate the role of ESR1 CpG island (CGI) methylation in ERα expression in canine mammary tumors. Twenty-one canine mammary samples were sorted into three groups: malignant tumor (n = 9), benign tumor (n = 8), and normal gland (n = 4). Immunohistochemical analysis and reverse-transcription quantitative real-time PCR were performed to assess ERα expression and ESR1 mRNA levels. The methylation status was determined using sodium-bisulfite-treated DNA sequencing. All normal mammary glands and benign tumors showed high ERα expression (score range, 5-8). Six of the nine malignant tumors did not show ERα expression (score 0), two had score 2, and one had score 4. Lower ERα ( P < .005) and ESR1 mRNA levels ( P < .005) were found in malignant mammary tumors than in the other two groups. Canine ESR1 has an intragenic and non-promoter-associated CGI, different from humans. No significant variation in methylation percentage was observed among the groups, suggesting that ESR1 is not regulated by DNA methylation, unlike that in humans. This difference should be considered in further research using ERα as a biomarker for mammary tumors in canine studies on ERα-targeting therapy.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

DNA Methylation Status of the Estrogen Receptor α Gene in Canine Mammary Tumors

et al. 2018

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“…Furthermore, studies have found that dogs with CMC have higher levels of estrogens in the blood, except in IMC, where the serum estrogens levels are lower than in dogs with other malignant mammary tumors ( 89 , 90 ). On the other hand, ER, PR, PRL, PRL receptor, and GH receptor have been found to be downregulated in malignant mammary tumors compared to normal mammary gland ( 91 , 92 ) and benign tumors ( 92 – 94 ). Furthermore, lymphatic invasion, high mitotic index, large tumor size, and tumor grade are significantly associated with low ER/PR expressions.…”

Section: Adjuvant Targeted Therapiesmentioning

confidence: 99%

From Conventional to Precision Therapy in Canine Mammary Cancer: A Comprehensive Review

et al. 2021

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Canine mammary tumors (CMTs) are the most common neoplasm in intact female dogs. Canine mammary cancer (CMC) represents 50% of CMTs, and besides surgery, which is the elective treatment, additional targeted and non-targeted therapies could offer benefits in terms of survival to these patients. Also, CMC is considered a good spontaneous intermediate animal model for the research of human breast cancer (HBC), and therefore, the study of new treatments for CMC is a promising field in comparative oncology. Dogs with CMC have a comparable disease, an intact immune system, and a much shorter life span, which allows the achievement of results in a relatively short time. Besides conventional chemotherapy, innovative therapies have a large niche of opportunities. In this article, a comprehensive review of the current research in adjuvant therapies for CMC is conducted to gather available information and evaluate the perspectives. Firstly, updates are provided on the clinical–pathological approach and the use of conventional therapies, to delve later into precision therapies against therapeutic targets such as hormone receptors, tyrosine kinase receptors, p53 tumor suppressor gene, cyclooxygenases, the signaling pathways involved in epithelial–mesenchymal transition, and immunotherapy in different approaches. A comparison of the different investigations on targeted therapies in HBC is also carried out. In the last years, the increasing number of basic research studies of new promising therapeutic agents on CMC cell lines and CMC mouse xenografts is outstanding. As the main conclusion of this review, the lack of effort to bring the in vitro studies into the field of applied clinical research emerges. There is a great need for well-planned large prospective randomized clinical trials in dogs with CMC to obtain valid results for both species, humans and dogs, on the use of new therapies. Following the One Health concept, human and veterinary oncology will have to join forces to take advantage of both the economic and technological resources that are invested in HBC research, together with the innumerable advantages of dogs with CMC as a spontaneous animal model.

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“…Hormone receptor expression is significantly reduced in malignant breast tumours, compared to non-neoplastic tissue and benign neoplasia. Among histological subtypes, minimal expression levels of estrogen receptor genes (ESR1), progesterone (PGR), and prolactin (PRLR) have been established in solid, anaplastic, and ductal cancers (Mohr et al, 2016). Canadas-Sousa et al (2019) identified genetic profiles, in particular ESR1 (rs397512133, rs397510462, rs851327560, rs397510612, rs852887655, rs852684753, rs852398698) associated with the later development of neoplasms of lactic pathology: significant tubular differentiation, and low dog-adjusted prognostic index (vet-NPI).…”

Section: Clinical and Ecological Aspects Of Biology Of Breast Neoplasmentioning

confidence: 99%

A modern look at the molecular-biological mechanisms of breast tumours in dogs

Bilyi

Gerdeva

Samoilіuk

et al. 2020

Regul. Mech. Biosyst.

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High morbidity and increase in the number of registrations of breast tumours in dogs, their wide application as biological models, discussion of numerous questions of oncogenesis, and the lack of a uniform/unified methodological approach to the study of molecular and biological mechanisms of treatment of cancer determine the relevance of the problem of cancer both in humans and in our domestic companions. The analysis of publications allowed us to establish the following patterns of carcinogenesis. The peculiarities of the biological behaviour of breast tumours depend on their pathomorphological structure. Genetic predisposition to breast cancer is characteristic only in the single breed aspect. Environmental factors are of critical relevance to carcinogenesis : chemical pollutants initiate oncogenesis indirectly – by altering the expression of several receptors, impaired endocrine balance and direct mutagenic effects. Reproductive status plays a key role in the initiation and progression of breast tumours by reducing the expression of estrogen, progesterone and prolactin receptor genes. The inflammatory response that accompanies the neoplasia process is characterized by increased production of cytokines, cyclooxygenase-2, interleukins (IL-1, IL-6, IL-8), vascular endothelial growth receptors, and impaired hemostatic status (oxidative stress), which promotes progression of disease. In breast cancer in dogs, genomic instability leads to genomic aberrations, and subsequently, mutations that support the proliferation, survival and dissemination of neoplastic cells. The initiation and progression of mammary gland tumours is provided by cancer stem cells by disrupting the regulation of precursor cell self-renewal, which also predispose to resistance to chemotherapeutic agents, radiation, and hormonal cancer therapy. The analysis of the publications revealed the major markers of carcinogenesis that could potentially be used as biological targets for the design of modern diagnostic strategies and high-performance therapeutic protocols.

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Hormone Receptor Expression Analyses in Neoplastic and Non-Neoplastic Canine Mammary Tissue by a Bead Based Multiplex Branched DNA Assay: A Gene Expression Study in Fresh Frozen and Formalin-Fixed, Paraffin-Embedded Samples

Cited by 14 publications

References 34 publications

DNA Methylation Status of the Estrogen Receptor α Gene in Canine Mammary Tumors

DNA Methylation Status of the Estrogen Receptor α Gene in Canine Mammary Tumors

From Conventional to Precision Therapy in Canine Mammary Cancer: A Comprehensive Review

A modern look at the molecular-biological mechanisms of breast tumours in dogs

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