MDC1: central regulator of estrogen receptor function and therapy response in lobular carcinoma.

Not all breast cancer has the same make up and those differences mean they do not all respond similarity to treatments. In spite of invasive lobular breast cancer (ILC) accounting for 10-15% of all breast cancer occurrences (~40,000 U.S. women diagnosed annually), it is understudied and treated the same as invasive ductal breast cancer. ILC is sometimes less responsive to chemotherapy, is difficult to detect on imaging, and patients with ILC are at a higher risk of long-term recurrence after treatment with anti-estrogens. ILC specific treatments are needed, which requires understanding the fundamental biology of ILC. Recent research from the Sikora Lab indicates that a particular protein (MDC1) may hold answers, and a new grant from the National Cancer Institute will support the lab’s effort to dissect the role of MDC1 in ILC biology.

This 5-year research project focuses on determining how MDC1 plays a unique role in ILC biology through interaction with estrogen receptors (ER) in the cell, to understand why ILC develops resistance to treatment. ILC typically leverages the hormone estrogen, which activates ER to promote ILC growth and disease progression. Anti-estrogen treatments that turn off the estrogen receptor help to keep ILC from growing, however, with time, ILC becomes resistant to ER focused treatment. The Sikora Lab has found that MDC1 has a unique function in ILC cells to facilitate ER activity and ER promotion of ILC growth and progression. MDC1 normally plays an important role in the repair of DNA (termed DNA damage response: DDR), but this ILC-specific interaction with ER is not yet well understood. The novel aspects of this new research are two fold: 1) the focus on specific ILC biology, and 2) study of the unique role of MDC1 in ILC.

The research has three aims that are interrelated.

The first investigates the relationship (that is, the physical interaction) between the estrogen receptor and MDC1 in ILC, as well as other proteins that may partner in their interaction. This is critical for understanding basic cell biology of ILC and the role of MDC1. It is important for patients because it will open new research pathways for investigators researching ILC. More specifically, it may identify biochemical mechanisms that make ILC cells distinct versus other types of breast cancer and open up new potential treatment targets.

The second aim explores how MDC1 controls ER’s access to and control of the ILC genome. The Sikora Lab established that MDC1 is critical in influencing ER binding to DNA, which ultimately will determine how ER controls the cancer’s behavior and therapy response. The focus of the research is on determining why MDC1 interacts with the genome where it does and what other proteins are important in ER+MDC1 activity in regulating the genome. Understanding this process and other key genes and gene complexes will be important to be able to linklaboratory data on ER+MDC1 to clinical/tumor data from ILC and outcomes information for patients with ILC.

The final (third) aim will define how DNA damage response changes through the unique interaction of MDC1 and ER in ILC. The expectation is that in ILC, activation of the estrogen receptor causes MDC1 to stop performing its role in the DNA damage response. Results will provide insight into how DDR may be controlled differently in ILC cells, and identify alternative treatment options specific to ILC based on targeting DNA repair.

Importantly, this new grant for the Sikora Lab is one of only ~5 grants currently funded by the National Institutes of Health specifically focused on the biology of lobular breast cancer, making this work critical for advancing knowledge and treatment of invasive lobular breast cancer.