Abstract
BackgroundDogs spontaneously develop invasive mammary carcinoma with a high prevalence of the triple-negative (TN) subtype (lack of ER-Estrogen Receptor and PR-Progesterone Receptor expression, lack of HER2-Human Epidermal Growth Factor Receptor 2 overexpression), making this animal model relevant for investigating new therapeutic pathways. Insulin-like growth factor Type-1 receptor (IGF1R) is frequently overexpressed in primary human breast cancers, with a growing role in the TN phenotype. The purpose of this study was to investigate the Dog as a candidate model for IGF1R-overexpressing mammary carcinoma.Methods150 bitches with canine mammary carcinoma (CMC) and a known 2-year follow-up were retrospectively included. IGF1R expression was assessed by immunohistochemistry (IHC) using a similar scoring system as for HER2 in breast cancer. The prognostic value of the IGF1R expression was assessed in terms of overall and specific survival as well as disease-free interval (DFI).Results47 CMC (31 %) were classified as luminal and 103 (69 %) as triple-negative (TN-CMC). 41 % of CMC overexpressed IGF1R (IHC score 3+) of which 76 % were TN-CMC and 62 % grade III. IGF1R overexpression was associated with aggressive features including lymphovascular invasion, histological grade III, low ER expression and the TN phenotype. Univariate and multivariate analyses revealed that IGF1R overexpression was associated with shorter overall and specific survivals and shorter DFI in TN-CMC.ConclusionsIGF1R overexpression is common and related to a poor outcome in canine invasive mammary carcinoma, particularly in the triple negative subtype, as in human breast cancer. Preclinical studies using the Dog as a spontaneous animal model could be considered to investigate new therapies targeting IGF1R in triple-negative breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1670-6) contains supplementary material, which is available to authorized users.
Highlights
Dogs spontaneously develop invasive mammary carcinoma with a high prevalence of the triple-negative (TN) subtype, making this animal model relevant for investigating new therapeutic pathways
Insulin-like growth factor Type-1 receptor (IGF1R) expression is highly related to prognosis in breast cancer, with a prognostic value dependent on the Estrogen receptor (ER) status of the tumors: in ERpositive breast cancer, IGF1R overexpression is related to favorable outcome [18] as opposed to ER-negative carcinomas, in which IGF1R overexression is associated with a poor outcome [19]
The 150 invasive carcinomas were classified as Luminal and Triple Negative according to ER, Progesterone receptor (PR) and Human epidermal growth factor receptor 2 (HER2) expressions [4, 5]: 47 (31.3 %) were of Luminal subtype (ERα ≥ 10 % and/or PR ≥ 10 %), of which 17 were Luminal-A (Ki-67 < 20 %) and 30 were Luminal-B (Ki-67 ≥ 20 %), and 103 (68.7 %) were classified as Triple Negative (ERα < 10 %, PR < 10 %, HER2 score other than 3+), of which 70 were basal-like (Cytokeratin-CK 5/6 and/or Epidermal Growth Factor Receptor-Epidermal growth factor receptor (EGFR) positive), and 33 were non-basal-like (CK 5/6 and EGFR negative)
Summary
Dogs spontaneously develop invasive mammary carcinoma with a high prevalence of the triple-negative (TN) subtype (lack of ER-Estrogen Receptor and PR-Progesterone Receptor expression, lack of HER2-Human Epidermal Growth Factor Receptor 2 overexpression), making this animal model relevant for investigating new therapeutic pathways. In various human cancers including breast cancer, the Insulin-like Growth Factor (IGF) family is closely related to oncogenesis [9, 10], in situ tumor growth [11], invasion and metastasis [11], with IGF1R (Insulin-like Growth Factor Type 1-Receptor) acting as a real oncogene and being overexpressed in more than 50 % of primary breast cancers [12] This is true for the TN breast cancer cells (estrogen-unresponsive), in which IGF1R is largely expressed and IGF-1 stimulates proliferation and survival, making them responsive in vitro to anti-IGF1R therapies [13, 14]. IGF1R expression is highly related to prognosis in breast cancer, with a prognostic value dependent on the ER status of the tumors: in ERpositive breast cancer, IGF1R overexpression is related to favorable outcome [18] as opposed to ER-negative carcinomas, in which IGF1R overexression is associated with a poor outcome [19]
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