Triple-negative vimentin-positive heterogeneous feline mammary carcinomas as a potential comparative model for breast cancer.

BACKGROUND: Human breast cancer is a heterogeneous disease classified by molecular subtyping into luminal A, luminal B, HER2-overexpressing, basal-like, claudin-low and normal-breast like. The routinely applied and standardized immunohistochemical-based surrogates of this classification group together the last three entities as triple-negative breast cancer (TNBCs) that show the most diverse and complex heterogeneity and represent a therapeutic challenge. In the present work 156 feline mammary lesions consisting of feline mammary carcinomas (FMCs), benign neoplasms, and hyperplastic/dysplastic tissues were evaluated histologically and by immunohistochemistry for expression of basal and luminal cytokeratins (CK), vimentin, alpha-smooth muscle actin, calponin, estrogen receptor (ER) alpha (a), and progesterone receptor (PR). Thirty-seven FMCs with 27 matched non-neoplastic controls were also investigated for gene expression of ERa, ER beta, PR, and HER2. RESULTS: A large group of hormone receptors (HRs)-negative aggressive carcinomas - that did not overexpress HER2 - could be distinguished from the less aggressive (10.8%) and benign (8%) HRs + tumors, that showed bilineage (luminal and myoepithelial) differentiation. Immunohistochemical evaluations of cytoplasmic filaments indicated that HRs- FMCs are vimentin+, CK14+, and CK5_6+ carcinomas that may resemble the TNBCs (basal like/claudin low) described in women. The identification of luminal and myoepithelial progenitors within the mammary ductal system suggested potential cells/sites of origin of these tumors. A diffuse and never previously described CKs/vimentin luminal cell co-expression was detected in the non-neoplastic ducts, indicating a potential bilineage progenitor. CONCLUSIONS: These results indicate and potentially explain the high incidence of triple-negative, vimentin + aggressive tumors in cats that may used to elucidate some of the challenging features of TNBCs in women.

Full-length sequence and expression analysis of estrogen receptor alpha mRNA in feline mammary tumors.

We report here on the isolation and sequencing of feline estrogen receptor alpha (ER-alpha) mRNA. Feline ER-alpha showed three alternative 5' untranslated exons and a common transcript of 6183 base pairs (bp). The putative coding sequence (1788 bp) and the unusually long 3' untranslated (3'-UTR) region (4305 bp) displayed high sequence similarity with human ER-alpha. A highly conserved sequence block was found in the 3'-UTR corresponding to a putative regulatory element for mRNA stability. In addition to wild-type ER-alpha mRNA, several exon-deleted splicing variants (ERDeltaE2, ERDeltaE3, ERDeltaE4, ERDeltaE5, ERDeltaE6, ERDeltaE7) were found in various feline tissues. This is similar to what observed in human tissues and opposite to the near absence of exon-deleted isoforms in rodents. Expression analysis of exon-deleted variants was also conducted on 24 samples of feline mammary carcinoma (FMC) and 15 normal mammary gland (NMG) controls, using a "splice targeted approach". The prevalence of some variants was similar for human and feline ER-alpha, while other isoforms were expressed at different frequencies in the two species. Two of the most frequent isoforms (ERDeltaE4, ERDeltaE7) were significantly less frequent in FMCs than in NMGs, likely as a consequence of decreased expression of ER-alpha in FMCs.