The investigation of transcriptional repression mediated by ZEB2 in canine invasive micropapillary carcinoma in mammary gland

Gamba, Conrado de Oliveira; Damasceno, Karine Araújo; Ferreira, Izabel Cristina Pereira Vaz; Rodrigues, Michele Ângela; Gomes, Dawidson Assis; Alves, Mariana Resende; Ferreira, Ênio; Cassali, Geovanni Dantas

doi:10.1371/journal.pone.0209497

Cited by 7 publications

(7 citation statements)

References 48 publications

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“…EMT involves a range of transcription factors, including zinc finger E-box-binding homeobox 1 and 2 (ZEB1 and ZEB2), Snail, signal transducer and activator of transcription 3 (STAT3), and Twist, as well as transcriptional targets such as transforming growth factor-β (TGF-β), all of which suppress the expression of epithelial-associated molecules (E-cadherin and membranous β-catenin) and promote molecules associated with mesenchymal cell phenotypes (N-cadherin, cytoplasmic β-catenin, fibronectin, and vimentin) ( 255 , 256 ). In CMC, Snail and ZEB2 have been proven to be related to E-cadherin downregulation in invasive micropapillary carcinomas ( 257 , 258 ).…”

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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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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“…IMPC of the breast is a morphologically distinct form of invasive ductal carcinoma that occurs in women [2]. The constituent tumor cells are typically arranged in small clusters with a central lumen, and micropapillae lacking brovascular cores extend into clear spaces [2,6,29]. This type of cancer in women is extremely aggressive, and based on previous studies from our group, it appears to exhibit a similar behavior in dogs [1,5,6,8].…”

Section: Discussionmentioning

confidence: 77%

“…IHC was performed as previously described with minor modi cations [9,29]. Sections (4 μm) of primary tumors were mounted on silanized slides, and a peroxidase-based detection system, Novolink™ Polymer (Leica Biosystems Newcastle Ltd., Newcastle, UK), was applied.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Characterization of neoplastic cells outlining the cystic space of invasive micropapillary carcinoma of the canine mammary gland.

Rodrigues

Caldeira-Brant

Gomes

et al. 2021

Preprint

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Background: Invasive micropapillary carcinoma (IMPC) is a rare malignant breast tumor and a variant form of invasive ductal carcinoma that is an aggressive neoplasm of the human breast and canine mammary gland. The importance of the tumor microenvironment in cancer development has gradually been recognized, but little is known about the cell types outlining the cystic space of canine IMPC. This study aimed to characterize the neoplastic cells outlining the cystic space of IMPC.Methods: Immunohistochemistry (IHC), immunofluorescence (IF), superresolution and transmission electron microscopy (TEM) were used to assess the cell types in the cystic areas of IMPCs.Results: Cells expressing the mesenchymal markers alpha-smooth muscle actin (aSMA), Vimentin, and S100A4 outlined the cystic space of IMPC. Furthermore, loss of epithelial cell polarity in IMPC was shown by the localization of MUC1 at the stroma-facing surface. This protein modulates lumen formation and inhibits the cell-stroma interaction. Immunohistochemical and IF staining for the myoepithelial cell marker p63 were negative in IMPC samples, and TEM revealed morphological aspects of myoepithelial-like cells with thin cytoplasmic extensions outlining the cystic space.Conclusions: The cells outlining the cystic space of IMPC in the canine mammary gland were characterized using IHC, IF and TEM. The presence of cells expressing aSMA, Vimentin, and S100A4 in the IMPC stroma suggested a role for tumor-associated fibroblasts in the IMPC microenvironment. The reversal of cell polarity revealed by the limited basal localization of MUC1 may be an important factor contributing to the invasiveness of IMPC. For the first time, the cystic space of canine mammary gland IMPC was shown to be delimited by myoepithelial-like cells that had lost p63 expression. These findings may enhance our understanding of the cellular microenvironment of invasive tumors to improve cancer diagnosis and treatment.

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“…IMPC of the breast is a morphologically distinct form of invasive ductal carcinoma that occurs in women [ 2 ]. The constituent tumor cells are typically arranged in small clusters with a central lumen, and micropapillae lacking fibrovascular cores extend into clear spaces [ 2 , 6 , 27 ]. This type of cancer in women is extremely aggressive, and based on previous studies from our group, it appears to exhibit a similar behavior in dogs [ 1 , 5 , 6 , 8 ].…”

Section: Discussionmentioning

confidence: 99%

Characterization of neoplastic cells outlining the cystic space of invasive micropapillary carcinoma of the canine mammary gland

et al. 2021

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Background Invasive micropapillary carcinoma (IMPC) is a rare malignant breast tumor and a variant form of invasive ductal carcinoma that is an aggressive neoplasm of the human breast and canine mammary gland. The importance of the tumor microenvironment in cancer development has gradually been recognized, but little is known about the cell types outlining the cystic space of canine IMPC. This study aimed to characterize the neoplastic cells outlining the cystic space of IMPC. Results Immunohistochemistry (IHC), immunofluorescence (IF), superresolution and transmission electron microscopy (TEM) were used to assess the cell types in the cystic areas of IMPCs. Cells expressing the mesenchymal markers alpha-smooth muscle actin (αSMA), Vimentin, and S100A4 outlined the cystic space of IMPC. Furthermore, loss of epithelial cell polarity in IMPC was shown by the localization of MUC1 at the stroma-facing surface. This protein modulates lumen formation and inhibits the cell-stroma interaction. Immunohistochemical and IF staining for the myoepithelial cell marker p63 were negative in IMPC samples. Furthermore, associated with peculiar morphology, such as thin cytoplasmic extensions outlining cystic spaces, was observed under TEM. These observations suggested cells with characteristics of myoepithelial-like cells. Conclusions The cells outlining the cystic space of IMPC in the canine mammary gland were characterized using IHC, IF and TEM. The presence of cells expressing αSMA, Vimentin, and S100A4 in the IMPC stroma suggested a role for tumor-associated fibroblasts in the IMPC microenvironment. The reversal of cell polarity revealed by the limited basal localization of MUC1 may be an important factor contributing to the invasiveness of IMPC. For the first time, the cystic space of canine mammary gland IMPC was shown to be delimited by myoepithelial-like cells that had lost p63 expression. These findings may enhance our understanding of the cellular microenvironment of invasive tumors to improve cancer diagnosis and treatment.

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The investigation of transcriptional repression mediated by ZEB2 in canine invasive micropapillary carcinoma in mammary gland

Cited by 7 publications

References 48 publications

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

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

Characterization of neoplastic cells outlining the cystic space of invasive micropapillary carcinoma of the canine mammary gland.

Characterization of neoplastic cells outlining the cystic space of invasive micropapillary carcinoma of the canine mammary gland

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