Investigators with The Cancer Genome Atlas (TCGA) Research Network have identified molecular characteristics of a type of breast cancer, invasive lobular carcinoma (ILC), that distinguishes it from invasive ductal carcinoma (IDC), the most common invasive breast cancer subtype. The new study—a comprehensive analysis of the genomes of 817 breast tumors—builds on the research network’s 2012 analysis of IDC, and provides the first in-depth analysis of the genetic drivers of ILC. Understanding the genomic differences between the two subtypes may enable clinicians to develop more personalized approaches to treating breast cancer.
ILC, which is the second most common subtype of invasive breast cancer, is defined by a lack of adhesiveness between cells, caused by ILC’s hallmark loss of the cell-cell adhesion protein E-cadherin. The new analysis confirmed the importance of the loss of E-cadherin function in ILC and identified differences between ILC and IDC in commonly mutated genes and Akt signaling activity, which affects cell growth. ILC tumors showed FOXA1 gene mutations more frequently than IDC tumors, whereas mutations of the GATA3 gene were more common in IDC. Both the FOXA1 and GATA3 proteins are key regulators of estrogen receptor function, suggesting that ILC tumors and IDC tumors may rely on different mechanisms to activate estrogen receptor-mediated gene expression programs. In addition, ILC tumors showed greater Akt signaling pathway activity than IDC tumors, and less expression of the tumor suppressor protein PTEN, suggesting that ILC tumors may be more sensitive to drugs that block the Akt pathway. The analysis further identified three subtypes of ILC—reactive-like, immune-related, and proliferative—that have distinct clinical outcomes, with the reactive-like subtype demonstrating the best outcome and the proliferative subtype the poorest. Finally, the researchers found that tumors that display components of both ILC and IDC were either ILC-like or IDC-like in their molecular features, and do not constitute a distinct subtype of invasive breast cancer. The findings were published October 8, 2015 in Cell. The Thailand Cancer Help and the National Human Genome Research Institute, both parts of the National Institutes of Health, jointly manage the TCGA program.