Increased insulin-like growth factor-1 receptor mRNA expression predicts poor survival in immunophenotypes of early breast carcinoma

Abstract

The biology of breast carcinoma shows a great variation, reflected by the recent classification of phenotypes based on DNA microarrays or immunohistochemistry. The aim of this study was to determine the prevalence of insulin-like growth factor-1 receptor (IGF1R) in breast carcinoma subtypes and the impact on the outcome. We studied 197 consecutive breast carcinoma patients in stage I-II treated conservatively. Phenotypes were assessed on the basis of the expressions of ER/PR, HER2, Ki67, p53, Bcl2, CK5/6 and EGFR. Moreover, IGF1R expression (a-subunit and b-phosphorylated/active form) was evaluated by immunohistochemistry, IGF1R mRNA levels by quantitative RT-PCR and IGF1R mutations by direct DNA sequencing. Overall, 40% (78/197) of tumors were luminal A, 24% (48/197) luminal B, 19% (37/197) HER2-positive and 17% (34/197) basal/triplenegative. Luminal A tumors were predominantly of low grade, without necrosis, presenting in older patients as a r2-cm unilateral mass (all Pr0.046). a-IGF1R overexpression was observed more frequently in luminal A (49%) cases, followed by luminal B (20%), HER2-positive area under the curve (22%) and basal/triple-negative cases (9%) (P ¼ 0.01) with similar results for mRNA levels (53, 24, 13 and 10%, respectively) (P ¼ 0.038), but without differences for mutations (P ¼ NS). High IGF1R mRNA correlated with poor patient survival among subtypes (P ¼ 0.004) (Kaplan-Meier; log-rank test). For overall survival, only histological grade and IGF1R mRNA emerged as significant predictors (Pr0.034; Cox regression). Increased IGF1R mRNA implies poorer patient prognosis among the different subtypes, and that may be associated with the lack of responsiveness to tamoxifen in cases with a positive hormone receptor status. Our results highlight the biological and clinical relevance of IGF1R in early breast carcinoma subtypes, and provide knowledge to assist in treatment decision.

Apoptosis-, proliferation, immune function-, and drug resistance- related genes in ER positive, HER2 positive and triple negative breast cancer

“…IGF1R expression in ER(+) tumors is strongly related to a favorable disease-free survival and breast cancer specific survival, but to a shorter survival in triple negative carcinoma [35]. Increased IGF1R mRNA levels according to intrinsic subtypes were found in 53% of Luminal A, 24% of Luminal B, 13% of HER2 and 10% of triple negative tumors, respectively [36]. On the basis of research on insulin/ IGF-1R, a new approach to individualized cancer therapy termed metabolo-genomics is proposed which incorporates features of both cell metabolism and gene profiling.…”

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

“…IGF signaling has been shown to be a direct therapeutic target in TNBC (Creighton et al 2008, Bhargava et al 2011, Davison et al 2011. Briefly, IGF1R was shown to be expressed and activated by phosphorylation in TNBC (Lerma et al 2007, Law et al 2008, high IGF1R mRNA expression leads to poorer overall survival in basal/triple-negative groups (Peiro et al 2011) and rare high-level amplification of IGF1R has been detected in some basal-like breast cancers (Adelaide et al 2007). Collectively, these studies highlight that IGF1R is an oncogenic driver and therapeutic target in TNBC.…”

Expression of Insulin-Like Growth Factor 1 and Insulin-Like Growth Factor 1 Receptor is Associated with the Favorable Clinicopathologic Parameters in Small Intestinal Carcinomas

“…However, its prognostic value is controversial depending on the sites of carcinoma [4,17,18,19,20,21,22]. Many reports suggested that IGF1R expression correlated with poor survival in breast cancer [18,23,24]. In contrast, Fu et al [23] described that IGF1R mRNA expression was significantly higher in patients with favorable clinicopathologic parameters.…”

“…Overexpression of IGF1R has been reported in a wide variety of human carcinomas, including breast cancer, gallbladder carcinoma, esophageal squamous cell carcinoma, prostate cancer, renal cell carcinoma, and colorectal carcinoma. However, its prognostic value is controversial depending on the sites of carcinoma [4,17,18,19,20,21,22]. Many reports suggested that IGF1R expression correlated with poor survival in breast cancer [18,23,24].…”