MYC and Breast Cancer

Abstract

MYC is a key regulator of cell growth, proliferation, metabolism, differentiation, and apoptosis. MYC deregulation contributes to breast cancer development and progression and is associated with poor outcomes. Multiple mechanisms are involved in MYC deregulation in breast cancer, including gene amplification, transcriptional regulation, and mRNA and protein stabilization, which correlate with loss of tumor suppressors and activation of oncogenic pathways. The heterogeneity in breast cancer is increasingly recognized. Breast cancer has been classified into 5 or more subtypes based on gene expression profiles, and each subtype has distinct biological features and clinical outcomes. Among these subtypes, basal-like tumor is associated with a poor prognosis and has a lack of therapeutic targets. MYC is overexpressed in the basal-like subtype and may serve as a target for this aggressive subtype of breast cancer. Tumor suppressor BRCA1 inhibits MYC's transcriptional and transforming activity. Loss of BRCA1 with MYC overexpression leads to the development of breast cancer-especially, basal-like breast cancer. As a downstream effector of estrogen receptor and epidermal growth factor receptor family pathways, MYC may contribute to resistance to adjuvant therapy. Targeting MYC-regulated pathways in combination with inhibitors of other oncogenic pathways may provide a promising therapeutic strategy for breast cancer, the basal-like subtype in particular.

Keywords: BRCA1; MYC; basal-like subtype; breast cancer.

Figure 1.

MYC regulatory network in breast cancer. MYC is regulated in multiple levels in breast cancer cells. TGF-β and BRCA1—which can repress MYC gene expression and MYC’s transcriptional activity, respectively—are frequently inactivated by mutation or epigenetic mechanism in breast cancer. Yet, oncogenic pathways such as Ras, Wnt, Notch, ER-α, and EGFR/Her2 positively influence MYC expression or stability. Loss of tumor suppressors and activation of oncogenic pathways can cause MYC deregulation. Deregulated MYC promotes tumor growth, metastasis, and therapy resistance. BRCA1 = breast cancer susceptibility gene 1; TGF-β = transforming growth factor β; Ras = rat sarcoma; Wnt = wingless-type murine mammary tumor virus integration site family; ER-α = estrogen receptor α; EGFR = epidermal growth factor receptor; Her2 = human epidermal growth factor receptor 2.

Figure 2.

MYC mRNA is highly expressed in basal-like tumors. RNAs were extracted from 168 primary breast tumors and applied for microarray analysis (Agilent, Santa Clara, CA). Gene expression data were retrieved from the database after the Lowess normalization procedure and data filtering. Upregulated and downregulated genes were picked up by the significant analysis of microarray 2-classes unpaired t test. Unsupervised hierarchical clustering demonstrates segregation of MYC expression in discrete groups. Red = Caucasian; Black = African American.