PI3K Signaling in Tumor Cells and Stroma Regulates Breast Cancer Metastasis
Abstract
Breast cancer is a major public health problem in the United States, and the American Cancer Society estimates that 40,000 women died from this disease in 2017. Tumor metastasis is the major cause of mortality in human breast cancer, and effective treatment of metastatic disease will require a better understanding of the signaling mechanisms that drive breast cancer cell invasion (the ability of tumor cells to move away from the primary tumor and into surrounding tissue). The functions of an enzyme called phosphoinositide 3-kinase (PI3K) are strongly implicated in breast cancer. There are several different variants of PI3K expressed in cells; these variants are called PI3K isoforms. Based on work in our laboratory, we believe that a particular isoform of PI3K, called PI3Kbeta, plays several important roles in breast cancer. PI3Kbeta is required for tumor cell invasion, which is the first step of the metastatic process. Furthermore, mutation of PI3Kbeta in breast cancer cells inhibits the formation of lung metastases in a mouse model of metastasis. In addition to its role in tumor cells, PI3Kbeta plays critical roles in the function of immune cells called macrophages. Macrophages play multiple roles in the immune system, including the killing of bacteria and other pathogens and the stimulation of antibody-producing cells. However, in addition to these healthy roles, macrophages can cooperate with tumor cells to enhance tumor growth and metastasis. In breast cancer, macrophages are recruited to primary tumors. Tumor cell-macrophage interactions are critical for tumor cell invasion and metastasis. To study PI3Kbeta in animals, we produced a mouse that expresses a mutant PI3Kbeta in all of its cells, and we are making a mouse that expresses mutant PI3Kbeta just in macrophages. We have studied macrophages from the whole-animal mutant, and we find that these macrophages are defective in many behaviors that are required for the promotion of tumor cell invasion and metastasis. Excitingly, preliminary experiments show that metastasis of mouse tumor cells to the lung is inhibited in mice expressing mutant PI3Kbeta. This proposal is built upon these data and examines the role of PI3Kbeta in breast cancer from both sides: the tumor cells and the immune cells that modulate tumor cell behavior. With regard to PI3Kbeta signaling in tumor cells, we have already shown that mutation of PI3Kbeta reduces tumor cell metastasis in mice. We now propose experiments to define the cellular mechanisms that produce this result. With regard to PI3Kbeta signaling in immune cells, we have preliminary data showing defects in immune system function in vitro. We now propose experiments to study the role of immune system PI3Kbeta during breast cancer metastasis in vivo. Taken together, the two parts of our study could establish PI3Kbeta as an important new drug target for the treatment of metastatic disease. A better understanding of PI3Kbeta signaling in both tumor cells and immune cells will be useful for designing strategies to inhibit primary and secondary metastasis. Although inhibitors of PI3Kbeta have been developed, the existing clinical trials of PI3Kbeta inhibitors have focused on treating tumor growth. Our work might refocus future trials on the treatment of patients with metastatic disease and provide new insights into the treatment of this devastating disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910040XX0
Entities
People
- Jonathan M Backer
Organizations
- Albert Einstein College of Medicine
- United States Army