Immunostaining for p53 and p16CDKN2A Protein Is Not Predictive of Prognosis for Dogs with Malignant Mammary Gland Neoplasms

Abstract

Mammary gland tumors (MGTs) are common in dogs and show a variable clinical behavior that is difficult to predict. Currently, few immunohistochemical markers have been established to predict the prognosis of a canine MGT. However, p53 immunostaining has been variably reported to be prognostic for canine MGTs. Additionally, while p16CDK2NA protein (p16) immunostaining has been found to be prognostic for human breast cancers, this marker has never been evaluated as a prognostic marker for canine neoplasms. In the present study, the prognostic utility of p53 and p16 was evaluated in 35 canine malignant MGTs. It was observed that 19 (54%) dogs died due to their MGTs with an overall mean survival time (MST) of 882 days. Seven MGTs showed p53 immunostaining, but this was not significantly associated with death (4 of 7 vs. 15 of 28; p = 0.6) or MST (670 vs. 934 days; p = 0.57). Five dogs had MGTs with no p16 immunostaining, 28 MGTs had intermediate p16 immunostaining, and two MGTs had increased p16 immunostaining. Neither death due to MGT (4 of 5, 14 of 28, or 1 of 2; p = 0.28) nor MST (683, 927, and 307 days; p = 0.31) were significantly associated with p16 immunostaining. Interestingly, p53 immunostaining was significantly associated with an increase or loss of p16 immunostaining. This is the first time that p16 has been evaluated as a prognostic marker for canine neoplasms. While these results suggest that a proportion of canine MGTs develop by cellular mechanisms that alter both p53 and p16 expression, there was no evidence that defects in p53 or p16 alter the behavior of a MGT. Neither p53 nor p16 was found to significantly predict prognosis, although this could reflect the limited number of MGTs included in the study.

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

“…Mutations in the p53 gene are associated with more than half of all human cancers and have been described in multiple cancers in dogs ( 196 ), including mammary tumors ( 197 , 198 ). However, its expression and mutation status as prognostic factors in veterinary medicine are controversial: while some studies have found no correlation ( 199 , 200 ), other authors have associated higher levels of p 53 with poor overall survival ( 201 , 202 ).…”

p53, ER, and Ki67 Expression in Canine Mammary Carcinomas and Correlation With Pathological Variables and Prognosis

“…Previous studies have investigated the expression of p53 in CMTs by PCR (polymerase chain reaction) and/or immunohistochemistry, but its association with prognosis and malignancy is still controversial. 5,16,17,22 Earlier research found that p53-positive status was significantly related to poor tumor differentiation, higher mitotic count, invasive growth, and necrosis. 5,31 However, other studies on TP53 gene expression found that its expression profile could not be considered a marker for tumor aggressiveness in CMTs.…”

Validation of p53 Immunohistochemistry (PAb240 Clone) in Canine Tumors with Next-Generation Sequencing (NGS) Analysis

“…In the canine species, for which many studies are based on immunohistochemistry alone, altered p53 immunoexpression has been reported in different tumors, such as cutaneous hemangiosarcomas [12,13], mammary carcinomas [13][14][15], osteosarcomas [2,[16][17][18], liposarcomas [19], mast cell tumors [20], squamous cell carcinomas [21], transmissible venereal tumors [22], prostate cancer [23], and epithelial colorectal tumors [24]. Different monoclonal and polyclonal antibodies were used in these studies, and they had conflicting results in terms of both the extent of positivity and the correlation with prognosis.…”

“…Generally, in both human and veterinary medicine [14,19,26], a 10% cutoff for nuclear immunopositivity is used, but as there is disagreement among authors, where several cutoff values have been used for both humans [1,7] and dogs [12,15,18,27].…”