Role of IGF1R in Breast Cancer Subtypes, Stemness, and Lineage Differentiation

Abstract

Insulin-like growth factor (IGF) signaling is fundamental for growth and survival. A large body of evidence (laboratory, epidemiological, and clinical) implicates the exploitation of this pathway in cancer. Up to 50% of breast tumors express the activated form of the type 1 insulin-like growth factor receptor (IGF1R). Breast cancers are categorized into subtypes based upon hormone and ERRB2 receptor expression and/or gene expression profiling. Even though IGF1R influences tumorigenic phenotypes and drug resistance across all breast cancer subtypes, it has specific expression and function in each. In some subtypes, IGF1R levels correlate with a favorable prognosis, while in others it is associated with recurrence and poor prognosis, suggesting different actions based upon cellular and molecular contexts. In this review, we examine IGF1R expression and function as it relates to breast cancer subtype and therapy-acquired resistance. Additionally, we discuss the role of IGF1R in stem cell maintenance and lineage differentiation and how these cell fate influences may alter the differentiation potential and cellular composition of breast tumors.

Keywords: ER+; ERBB2+; IGF1R; breast cancer subtypes; lineages; luminal; triple negative.

Figure 1

Genomic and transcriptomic alterations in the IGF pathway in cancer. Data are from The Cancer Genome Atlas at cBio (http://www.cbioportal.org/) in February 2015. For several cancers, the data are published (pub) while for others it is provisional and in progress. (A) Histogram showing genomic changes (somatic base pair mutation and copy number alteration) in 13 members of the IGF pathway [notated on the y-axis in (B)]. Each bar represents the percentage of tumors, which show an alteration in these genes and each cancer type is indicated on the X-axis. (B) Genomic and transcriptomic changes (mRNA levels) specifically in breast cancer for 13 genes indicated on the y-axis. Each row represents a different gene. Each gray box represents an individual tumor. The percentage of tumors showing an alteration for each gene is shown on the Y -axis next to the gene. A red box indicates the gene is amplified and blue is deleted. A box with a red outline represents RNA overexpression compared to normal breast and blue is underexpression. A green dot represents a somatic base pair mutation. Tumors without an alteration in any of the IGF family members have been removed for visualization.

Figure 2

Expression levels of IGF pathway components across breast cancer subtypes. Level 3, IlluminaHiSeq_RNASeqV2 normalized gene expression values for all breast cancer tumors were downloaded from The Cancer Genome Atlas. The expressions of the indicated genes from tumors (columns) with calculated PAM50 scores (42) were extracted, log2 transformed, median centered for each gene (rows), and a heatmap was generated using MeV. The PAM50 subtype clusters are shown above with the indicated colors.