Feline mammary basal-like adenocarcinomas: a potential model for human triple-negative breast cancer (TNBC) with basal-like subtype

Abstract

Background: Breast cancer is one of the leading causes of cancer deaths. Triple-negative breast cancer (TNBC), an immunophenotype defined by the absence of immunolabeling for estrogen receptor (ER), progesterone receptor (PR) and HER2 protein, has a highly aggressive behavior. A subpopulation of TNBCs exhibit a basal-like morphology with immunohistochemical positivity for cytokeratins 5/6 (CK5/6) and/or epidermal growth factor receptor (EGFR), and have a high incidence of BRCA (breast cancer susceptibility) mutations. Feline mammary adenocarcinomas (FMAs) are highly malignant and share a similar basal-like subtype. The purpose of this study was to classify FMAs according to the current human classification of breast cancer that includes evaluation of ER, PR and HER2 status and expression of basal CK 5/6 and EGFR. Furthermore, we selected triple negative, basal-like FMAs to screen for BRCA mutations similar to those described in human TNBC.

Methods: Twenty four FMAs were classified according to the current human histologic breast cancer classification including immunohistochemistry (IHC) for ER, PR HER2, CK5/6 and EGFR. Genetic alteration and loss of heterozygosity of BRCA1 and BRCA2 genes were analyzed in triple negative, basal-like FMAs.

Results: IHC for ER, PR and HER2 identified 14 of the 24 (58%) FMAs as a triple negative. Furthermore, 11 of these 14 (79%) triple negative FMAs had a basal-like subtype. However, no genetic abnormalities were detected in BRCA1 and BRCA2 by direct sequencing and loss of heterozygosity analysis.

Conclusion: FMAs are highly aggressive neoplasms that are commonly triple negative and exhibit a basal-like morphology. This is similar to human TNBC that are also commonly classified as a basal-like subtype. While sequencing of a select number of triple negative, basal-like FMAs and testing for loss of heterozygosity of BRCA1 and BRCA2 did not identify mutations similar to those described in human TNBC, further in-depth evaluation is required to elucidate a potential role of BRCA in the tumorigenesis of triple negative, basal-like FMAs. The strong similarities in clinical behavior, morphology and IHC phenotype suggest that triple negative, basal-like FMAs may be a suitable spontaneous animal model for studying novel therapeutic approaches against human basal-like TNBC.

Figure 1

Identification of triple negative basal-like subtype (ER-, HER2-, CK5/6+ and/or EGFR+). Sections of feline mammary adenocarcinoma with basal-like (A) subtype were CK5/6 (B)and EGFR positive (C), but negative for estrogen receptor (D), progesterone receptor and HER2).

Figure 2

Identification of estrogen receptor-positive luminal A subtype (ER+, PR + or PR-, HER2-). Sections of feline mammary adenocarcinoma with tubular (A) and solid morphology were estrogen receptor positive (B) and HER2 negative (C), but focally positive for EGFR (D).

Figure 3

Identification of estrogen receptor-positive luminal B subtype (ER+, PR + or PR-, HER2+). Sections of feline mammary adenocarcinoma with tubular (A) and papillary morphology were estrogen receptor positive (B) and HER2 positive (C), but positive for CK5/6 (D).

Figure 4

Identification of HER2 overexpression subtype (ER-, HER2+). Sections of feline mammary adenocarcinoma with tubular and papillary (A) and solid morphology were estrogen receptor negative (B) and HER2 positive (C), but focally positive for CK5/6 (D).

Figure 5

Detection of loss of heterozygosity in BRCA1 and BRCA2. No allelic losses were detected in triple negative tumors exhibiting a basal-like phenotype.