Marginal activity of progesterone receptor B (PR-B) in dogs but high incidence of mammary cancer

Gračanin, Ana Gudelj; Voorwald, Fabiana Azevedo; Wolferen, Monique van; Timmermans-Sprang, Elpetra P. M.; Mol, Jan A.

doi:10.1016/j.jsbmb.2014.08.016

Cited by 5 publications

(3 citation statements)

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“…10,15 Compared with other animals, female dogs have a high incidence of mammary gland tumors, 3 times higher than that in women. 9,19,21,22,27,38 A high homology between human and female dog mammary tumors has been observed with regard to the natural occurrence, sites of metastasis, hormone dependence, and pathways involved in tumorigenesis. 22,34,36 In Brazil, the estimated prevalence of malignant canine tumors exceeds 70%, 31,32 higher than that reported in the United States, where the rate is approximately 50%.…”

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confidence: 99%

Downregulation of ATM Gene and Protein Expression in Canine Mammary Tumors

et al. 2016

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The ataxia telangiectasia mutated (ATM) gene encodes a protein associated with DNA damage repair and maintenance of genomic integrity. In women, ATM transcript and protein downregulation have been reported in sporadic breast carcinomas, and the absence of ATM protein expression has been associated with poor prognosis. The aim of this study was to evaluate ATM gene and protein expression in canine mammary tumors and their association with clinical outcome. ATM gene and protein expression was evaluated by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry, respectively, in normal mammary gland samples (n = 10), benign mammary tumors (n = 11), nonmetastatic mammary carcinomas (n = 19), and metastatic mammary carcinomas (n = 11). Lower ATM transcript levels were detected in benign mammary tumors and carcinomas compared with normal mammary glands (P = .011). Similarly, lower ATM protein expression was observed in benign tumors (P = .0003), nonmetastatic mammary carcinomas (P < .0001), and the primary sites of metastatic carcinomas (P < .0001) compared with normal mammary glands. No significant differences in ATM gene or protein levels were detected among benign tumors and nonmetastatic and metastatic mammary carcinomas (P > .05). The levels of ATM gene or protein expression were not significantly associated with clinical and pathological features or with survival. Similar to human breast cancer, the data in this study suggest that ATM gene and protein downregulation is involved in canine mammary gland tumorigenesis.

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confidence: 99%

Downregulation of ATM Gene and Protein Expression in Canine Mammary Tumors

et al. 2016

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“…There are two PR isoforms that are synthesized from the PR gene in both humans and dogs: PRA and PRB. In NCI-H295R cells, the predominant isoform of the PR is PRB (40), whereas in dogs PRB has been shown to have very limited transactivation potential (42). This difference in isoform activity between the two species could explain the contradictory results.…”

Section: Discussionmentioning

confidence: 98%

Dynamics of femtosecond laser-induced shockwaves at a water/air interface using multiple excitation beams

Vreugdenhil¹,

Oosten²,

Hernández-Rueda³

2018

Opt. Lett.

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Abiraterone acetate (AA) is a potent inhibitor of steroidogenic enzyme 17a-hydroxylase/17,20-lyase (CYP17A1). AA is approved for the treatment of prostate cancer but could also be used to treat patients with Cushing syndrome (CS). Similar to humans, canine glucocorticoid synthesis requires CYP17A1, providing a useful animal model. The objective of this study was to preclinically investigate the effect of AA on adrenocortical hormone production, cell viability, and mRNA expression of steroidogenic enzymes in canine primary adrenocortical cell cultures (n = 9) from the adrenal glands of nine healthy dogs. The cells were incubated with AA (0.125 nM to 10 mM) for 72 hours under basal conditions and with 100 nM ACTH(1-24). Adrenocortical hormone concentrations were measured in culture medium using liquid chromatography-mass spectrometry, RNA was isolated from cells for subsequent real-time quantitative PCR analysis, and cell viability was assessed with an alamarBlue™ assay. AA reduced cortisol (IC 50 , 21.4 6 4.6 nM) without affecting aldosterone under basal and ACTH-stimulated conditions. AA increased progesterone under basal and ACTH-stimulated conditions but reduced corticosterone under basal conditions, suggesting concurrent inhibition of 21-hydroxylation. AA did not affect the mRNA expression of steroidogenic enzymes and did not inhibit cell viability. In summary, primary canine adrenocortical cell culture is a useful model system for drug testing. For the treatment of CS, AA may to be superior to other steroidogenesis inhibitors due to its low toxicity. For future in vivo studies, dogs with endogenous CS may provide a useful animal model.

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“…Only the combination of dox plus P 4 changed the expression of over 600 genes, both in hPRB- and hBUScPRB-expressing cell lines. Only a minority of these genes were influenced by cPRB (41, 42). These results indicate a very limited transactivation potential of cPRB on endogenous genes, thereby questioning its role in mammary gland development and carcinogenesis.…”

Section: Progesteronementioning

confidence: 99%

Molecular Signaling of Progesterone, Growth Hormone, Wnt, and HER in Mammary Glands of Dogs, Rodents, and Humans: New Treatment Target Identification

2017

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Mammary tumors are the most common form of neoplasia in the bitch. Female dogs are protected when they are spayed before the first estrus cycle, but this effect readily disappears and is already absent when dogs are spayed after the second heat. As the ovaries are removed during spaying, ovarian steroids are assumed to play an essential role in tumor development. The sensitivity toward tumor development is already present during early life, which may be caused by early mutations in stem cells during the first estrus cycles. Later on in life, tumors arise that are mostly steroid-receptor positive, although a small subset of tumors overexpressing human epidermal growth factor 2 (HER2) and some lacking estrogen receptor, progesterone receptor (PR), and HER2 (triple negative) are present, as is the situation in humans. Progesterone (P4), acting through PR, is the major steroid involved in outgrowth of mammary tissue. PRs are expressed in two forms, the progesterone receptor A (PRA) and progesterone receptor B (PRB) isoforms derived from splice variants from a single gene. The dog and the whole family of canids have only a functional PRA isoform, whereas the PRB isoform, if expressed at all, is devoid of intrinsic biological activity. In human breast cancer, overexpression of the PRA isoform is related to more aggressive carcinomas making the dog a unique model to study PRA-related mammary cancer. Administration of P4 to adult dogs results in local mammary expression of growth hormone (GH) and wing less-type mouse mammary tumor virus integration site family 4 (Wnt4). Both proteins play a role in activation of mammary stem cells. In this review, we summarize what is known on P4, GH, and Wnt signaling in canine mammary cancer, how the family of HER receptors could interact with this signaling, and what this means for comparative and translational oncological aspects of human breast cancer development.

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Marginal activity of progesterone receptor B (PR-B) in dogs but high incidence of mammary cancer

Cited by 5 publications

References 50 publications

Downregulation of ATM Gene and Protein Expression in Canine Mammary Tumors

Downregulation of ATM Gene and Protein Expression in Canine Mammary Tumors

Dynamics of femtosecond laser-induced shockwaves at a water/air interface using multiple excitation beams

Molecular Signaling of Progesterone, Growth Hormone, Wnt, and HER in Mammary Glands of Dogs, Rodents, and Humans: New Treatment Target Identification

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