Steffi Oesterreich, PhD

Understanding the biology of invasive lobular carcinoma, a common but understudied form of breast cancer.

Impact

Invasive lobular carcinoma (ILC) is a type of invasive breast cancer that originates in the milk-producing glands of the breast called lobules and accounts for 10 to 15 percent of diagnoses. The key difference between ILC and invasive ductal cancer (IDC), is the loss of E-cadherin, a protein that is present on the surface of cells and mediates attachment to other cells. How this molecular hallmark of ILC drives disease function is still an open research question. A rarer and more aggressive form of ILC called pleomorphic ILC (pILC) is also poorly understood due to a lack of large, well-characterized studies. Patients with pILC have significantly worse outcomes than those with classic ILC.

Progress Thus Far

The team has developed an innovative new laboratory model in an attempt to “switch” an ILC tumor into an IDC tumor by restoring E-cadherin expression. In doing so, the team aims to identify characteristics in ILC that are driven by changes other than E-cadherin levels. Preliminary results indicate that overexpression of E-cadherin in ILC alone is not sufficient to “switch” subtype, implying there may be additional factors that drive biological and clinical differences between the two.

They have further discovered a protein called AP-2B, which controls the activity of many genes, is present at much higher levels in ILC tumors. Using laboratory models, they showed that lowering AP-2B levels makes lobular cancer cells stop growing and even die, suggesting AP-2B helps ILC cells survive and may be a critical driver of ILC development. The team has found early evidence that AP-2B may influence how cancer cells process fats and energy, a direction they will actively explore going forward.

In a second, newly launched project, the team has assembled a carefully reviewed collection of 38 pILC tumor samples, one of the largest of its kind to date. An early and striking finding is that 30% of these tumors show notable immune cell activity, which is surprisingly high, since estrogen receptor-positive cancers like pILC are typically considered “immune cold” and unlikely to respond to immunotherapy. This raises the possibility that pILC may be more treatable with immunotherapy than previously thought.

What’s next

In the coming year, the team will pursue two goals. First, to understand what AP-2B does in lobular cancer, the team will map the genes AP-2B controls, how it interacts with other key cancer proteins, and whether it rewires the cancer cell’s identity at the earliest disease stage. They will then test whether targeting AP-2B or its interacting pathways could serve as a new treatment strategy. Second, to build the most comprehensive molecular picture of pILC to date. Using state-of-the-art DNA and RNA analysis tools, the team will identify the genetic mutations and gene activity patterns that drive pILC’s aggressiveness, distinguish it from classic ILC, and reveal potential targets for new treatment.