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

Diego Caliari,Federica Frassineti,Roberta Rasotto,Valentina Zappulli,Barbara Cardazzo,Michael H Goldschmidt,Massimo Castagnaro

doi:10.1186/s12917-014-0185-8

Abstract

BackgroundHuman 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.ResultsA 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.ConclusionsThese 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.

Highlights

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
We demonstrated the distribution of cell subtypes – both luminal epithelial and basal/myoepithelial lineages – in non-neoplastic glands, and found an unusual and previously undocumented ductal luminal VIM positivity and a luminal CK14 expression located in the terminal intra-lobular ducts
In our work we evaluated HER2 by RT-PCR and we found no significant difference in HER-2 expression between feline mammary carcinomas (FMCs) and matched non-neoplastic tissues

Summary

Introduction

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. Guidelines for IHC markers (i.e. ER, PR, HER2, Ki67) evaluation are continuously under discussion to stratify breast cancer patients in a clinical context for prognostic and treatment selection purposes [6,7,8]. When applying both clinical and IHC analysis to HBC a group of “triple negative” cancers (TNBCs) (lacking ER, PR, and HER2) is identified [9]. Using transcriptome analysis distinct classes of TNBCs have been recognized: the BLBCs, the normal breast-like HBCs, and the newly identified claudin-low subtype [12,13], but further efforts dissected even more distinct TNBCs signatures [10]

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