Dr. Bravo-Cordero on the Role of the Extracellular Matrix in Breast Cancer Dormancy

Jose Javier Bravo-Cordero, MD, associate professor of medicine, hematology, medical oncology, Icahn School of Medicine, Mount Sinai, discusses the role of extracellular matrix (ECM) proteomics and disseminating tumor cells (DTCs) when regulating the tumor microenvironment to induce dormancy in breast cancer.

It is common for patients with breast cancer who have undergone surgery prior to tumor metastasis recur 5 and 10 years later. Research on tumor dissemination and metastasis has revealed that cancer cells can migrate from the primary tumor site to a patient’s secondary organs early on in tumor development, Bravo-Cordero says. However, the cancer cells do not immediately begin proliferation upon arrival, he notes. Instead, these cells enter a period of tumor dormancy prior to being activated. Clinical efforts to identify the activating proteins involved in regulating cancer cell proliferation have specifically focused on the interaction between the ECM and key metastatic sites in disseminated cancer cells.

Clinical research efforts have revealed that dormant cancer cells express a specific set of ECM genes responsible for secreting several components at metastatic organs, Bravo-Cordero continues. For example, tumor-derived COL3A1, a fibrillar collagen protein, has been identified for its contribution to structural changes preceding the transition from dormant to active status. COL3A1 is considered vital to the assembly of a pro-quiescence ECM, and therefore may be required to prevent tumor cells from metastasizing.

Moreover, DTCs in breast cancer manage and modify the tumor microenvironment through the coordination of efficient, migratory movement and proliferation at secondary tumor sites. A population DTCs have been identified in primary breast tumors that modify the microenvironment in favor of both cell dissemination and tumor dormancy.

Tumor cells do not efficiently regulate the GTPase activator, srGAP1, which allows the tumor cells to efficiently migrate from blood vessels. However, cells with low expression of srGAP1 do not re-enter the cell cycle at the secondary tumor site. This is because srGAP1 controls key dormancy pathways for breast cancer tumors cells, includes increasing levels of transforming growth factor beta receptor type II (TGFB), which inhibits tumor suppression of the TGFB pathway and allows for proliferation, Bravo-Cordero concludes.