MYC in breast tumor progression

Abstract

Breast cancer is the second leading cause of cancer deaths and is the most frequently diagnosed cancer in women of industrialized nations. Breast cancer progression is a multistep process involving genetic and epigenetic alterations that drive normal breast cells into highly malignant derivatives with metastatic potential. MYC is a proto-oncogene whose protein product contains a basic helix-loop-helix domain. MYC functions as a transcription factor regulating up to 15% of all human genes. MYC is regulated at multiple levels, and the protein is a downstream effector of several signaling pathways. In breast cancer cells, MYC target genes are involved in cell growth, transformation, angiogenesis and cell-cycle control. BRCA1 is linked to transcriptional regulation through interaction with MYC. Although the relationship between amplification and overexpression is not clearly delineated, MYC amplification is significantly correlated with aggressive tumor phenotypes and poor clinical outcomes. MYC amplification is emerging as an important predictor of response to HER2-targeted therapies and its role in BRCA1-associated breast cancer makes it an important target in basal-like/triple-negative breast cancers.

Figure 1. Signal pathways modulating MYC expression and the potential cellular processes involved in breast tumor progression controlled by MYC

MYC gene transcription is activated by a variety of growth factors (Wnt and Notch are shown), yet repressed by other growth factors, such as TGF-β. The MYC-MAX dimer is required for MYC transcription activation function, and MYC-MAX interaction is modulated by other basic helix-loop-helix proteins, such as MAD. Functional MYC activates the expression of key factors involved in breast tumor progression.

Figure 2. Possible biological process that can be used for MYC-targeted therapy

Agents designed to reduce MYC gene expression at the levels of transcription and mRNA stability are being tested. MYC-MAX interaction, MYC protein degradation and interference with transcription of MYC-activated genes are promising fields for future drug design. *Less explored area of MYC-targeted therapy is MYC gene amplification.