Relationship between NF-κB Expression and Malignancy of Canine Mammary Gland Tumor Tissues

Abstract

AbSTRACT. In this study, the nuclear expression of nuclear factor kappa B (NF-κB) in 48 tissues specimens from 25 canine spontaneous mammary gland tumor (MGT) patients was assessed by immunohistochemistry to compare their levels with clinical features, histological types, prognostic outcomes and proliferative activities, including the mitotic index (MI) and cylcinD1 expression. Twelve of eighteen (66.7%) malignant tumor tissues showed greater than 10% nuclear staining, while benign tumor and hyperplastic tissues showed less than 10% nuclear staining. Higher nuclear expression of NF-κB was positively correlated with larger tumor size, lymph node metastasis and higher MI; however, no correlation was observed with distant metastasis and cyclin D1 expression. Higher NF-κB nuclear expression correlated with shorter patient survival. These findings suggest that NF-κB is a useful prognostic factor for canine MGT patients. KEY WORDS: canine MGT, immunohistochemistry, malignancy, NF-κB, prognosis.doi: 10.1292/jvms.11-0380; J. Vet. Med. Sci. 74(6): 713-718, 2012 Mammary gland tumor (MGT) is the most common type of tumor in intact female dogs [11]. The histological type of MGT tissues is strongly related to prognosis, with negative prognosis being associated with poorly differentiated tumors. Among the related factors, distant metastasis is the most significant, and dogs with distant metastasis have a worse prognosis than those with only regional lymph node involvement [15,17].Progression of breast cancer from a benign to a malignant phenotype is accompanied by overexpression of several growth factors, cytokines, and chemokines in cancer cells [22]. Some of these substances can induce the expression of prometastatic genes through nuclear factor kappa B (NF-κB) [22]. Elevated DNA binding activity of NF-κB was observed in breast cancer cell lines with invasive and metastatic growth properties [22]. The NF-κB complex is composed of a family of inducible transcription factors found in almost all cells [3,4,13], and this complex is generally recognized as an essential cell mediator acting "at the crossroads of life and death" [16]. The mammalian NF-κB family consists of 5 members: p50 (NF-κB1), p52 (NF-κB2), p65 (Rel A), c-Rel, and Rel B [23]. These Rel family members exist as homo-or heterodimers, and the most abundant form of intracellular NF-κB is generally the p50/p65 heterodimer [23]. In resting cells, NF-κB is cytoplasmically sequestered as a latent complex bound to one or more members of the IκB protein family (I-κBα, I-κBβ, I-κBε, I-κBγ, Bcl-3 and the precursor Rel proteins p100 and p105). Diverse cell stimuli induce phosphorylation (via activation of the I-κB kinase complex) and subsequent proteasomal degradation of I-κB inhibitory proteins, leading to the activation of NF-κB for nuclear translocation and DNA binding [23]. Nuclear traslocated NF-κB is reported to activate the transcription of many factors including cyclin D1, which is a key regulator of G1 checkpoint control [7,23].Information about the significance...

Relationship of the mucosal microbiota to gastrointestinal inflammation and small cell intestinal lymphoma in cats

“…Non‐specific binding was blocked by incubation of slides for 10 minutes with a protein‐blocking agent (Dako Products, Carpinteria, CA) before application of the primary antibody. Slides were then incubated overnight in a moist‐chamber with the following primary antibodies: canine cross‐reactive monoclonal antibody against NF‐κB (p65) (BD Transduction Laboratories, Lexington, KY)55 diluted 1 : 50, and a goat polyclonal to CD11b + (anti‐CD11b + antibody ‐ ref. N° ab62817) (ABCAM, San Francisco, CA) diluted 1 : 50.…”

Review: NF-kB activation in canine cancer

“…A study evaluating immunohistochemical labeling of NF-kB p65 in canine mammary tumors found that higher nuclear expression of NF-kB was correlated with larger tumor size, lymph node metastasis, and higher mitotic index, while there was no correlation with distant metastasis or cyclin D1 expression. 59 Another study identified an association between increased NF-kB activation and decreased surivival in dogs with mammary cancer. 54…”

Expression and significance of CHIP in canine mammary gland tumors

“…CHIP is known to be involved in ubiquitination and degradation of certain oncoproteins, such as NF-κB, SRC-3 and mutant p53 [ 17 , 18 , 25 , 32 ]. Previous research has shown that NF-κB is a useful prognostic factor for canine mammary gland tumor [ 24 ]. It regulates downstream genes, including IL-6 , IL-8 , MMP-2 , VEGF and cyclooxygenase-2 , to promote proliferation, survival, angiogenesis and metastasis of tumors [ 12 , 21 ].…”