Genetic and Functional Analysis of the Role of Clonal Tumor-Infiltrating Leukocytes in Breast Cancer Pathogenesis and Therapy
Abstract
Scatter weed seeds in a lush garden and the seeds are likely to grow into weeds. Try the same in the frigid artic soil and the seeds will wither and die. Breast cancer metastasis, whereby insidious cancer seeds spread from the breast to distant organs, is the primary cause of breast cancer mortality. Cancer research has long focused on what makes cancer cells multiply and in particular on identifying the mutations within the cancer cells that drive their growth. Only recently has research demonstrated that the environment or "soil" around the cancer cells is critical to how cancers thrive in distant organs. A key component of the tumor microenvironment is immune white blood cells, which may infiltrate both primary breast cancers as well as metastatic deposits. Indeed, evidence shows that the amount of infiltrating white blood cells may change the prognosis in breast cancer patients. While scientists have developed techniques to identify mutations in cancer cells, we asked a novel question: Do the immune cells that infiltrate a breast cancer harbor genetic mutations as well? In asking this question, we identified a potential major breakthrough in the prognostication and treatment of women with breast cancer. In a group of breast cancer patients with newly diagnosed breast cancer, we found a substantial number of women with mutations within the white blood cells that infiltrated their breast cancers. The mutations within these white cells are associated with hematologic malignancies, such as leukemia. Under the microscope, these immune cells looked relatively normal. However, by digging deeper and looking at the genetic composition of the immune cells, we found that some of these white cells actually were quite aberrational and harbored mutations associated with leukemia, even though the women did not have any signs of leukemia. In fact, when we looked at the white bloods cells circulating in their blood, those white cells did not have the same mutations that we found in the white cells infiltrating the cancers. We hypothesize that breast cancers intimately interact with mutated white blood cells and that this interaction may contribute to breast cancer initiation and/or progression and metastasis. Our objective is to better characterize the genetic make-up of tumor-infiltrating white blood cells in primary and metastatic breast cancers and to evaluate the functional interaction between these mutated white blood cells and breast cancer cells. To evaluate our hypothesis, (1) we will study a group of triple-negative breast cancer patients who are at high risk for recurrence. We will study the tumors in their breast as well as any metastatic sites that develop. (2) We will also use state-of-the-art experimental models to determine whether if we alter the white blood cells within a cancer can we stop metastatic spread and growth. Despite efforts to develop targeted therapies against breast cancer cells and decrease metastatic growth, breast cancer metastasis continues to drive mortality. We believe that targeting the mutated white blood cells within a cancer is a key step towards a cure for breast cancer. Our findings could be relevant to patients both at risk and with metastasis. Fundamentally, our hope and commitment to this work will be to reveal whether mutated white blood cells contribute to tumor growth and metastasis. If successful, our work would dramatically accelerate the end of breast cancer metastasis by targeting both the cancer cells as well as the infiltrating white cells. Our aim is to fundamentally render the "soil" surrounding cancer cells entirely inhospitable.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510549
Entities
People
- Elizabeth A Comen
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army