David N. Reisman M.D., Ph.D.

Lay Description

The long-term goal of our research is to develop treatments for bronchioalveolar carcinoma (BAC) and other lung cancers. To understand how to cure these diseases, we need to understand their biology. BAC patients constitute about 5% of the total lung cancer patients in the U.S. today; thus relatively little research has been dedicated to the understanding of the biology of this cancer, and even less into finding a cure. In fact, researchers lack even basic research models and tools to study this disease. The goal of this proposal is to adapt our preclinical model of lung cancer to study BAC and to gain insight into the biology of the disease by looking at two of the proteins we believe are involved. These proteins, BRM and BRG1, are part of a large protein complex, called SWI/SNF, which is known to be involved in regulating many cellular processes, including the growth of cells. Our research indicates that when SWI/SNF stops functioning, the cellular processes it regulates are drastically affected. In particular, cells can grow continuously in the absence of these regulatory proteins. Our laboratory has found that when the SWI/SNF components BRM and BRG1 stop functioning, they affect the ability of the regulatory protein Retinoid Acid Receptor (RAR) to do its work and stop excessive cell growth. Fortunately, we have also found that it is possible to restore the function of BRM. This suggests that BRM—and perhaps other components of SWI/SNF—could help slow, or stop, the growth of cancer-related cells, since restoring BRM’s function would also restore the function of RAR. To achieve this goal, we need to define exactly which components of SWI/SNF are affected in BAC and then determine how these alterations affect RAR. We will use two main approaches: first, we will identify specific genes involved in BAC, and second, we will induce lung cancer in our preclinical model to see how RAR function is changed when BRM and other subunits are removed. We believe this research will benefit BAC patients, not only by providing a means of understanding the biology of this disease, but also by giving us important insight into possible treatments.

Scientific Abstract

SWI/SNF is an important chromatin remodeling complex that serves a pivotal role in the regulation and control of gene expression. Transcription factors and key cellular proteins recruit this complex to a specific DNA domain where it either promotes and/or blocks gene expression by shifting the position of histone within the chromatin. The SWI/SNF complex was first definitively linked to tumorigenesis when it was found that its subunit, BAF47, is a bona fide tumor suppressor protein and the key event in the development of rhabdoid sarcoma, a lethal pediatric tumor. We have found that the ATPase subunits BRG1 and BRM, which are essential for complex function, are concomitantly lost in 30-40% of lung cancer cell lines and 10-20% of primary lung cancers as well as other solid tumors. Our preclinical studies have shown that the loss of either protein leads to increased cancer susceptibility by interfering with local growth control mechanism, such as retinoic acid receptors (RAR). These receptors are known to both inhibit proliferation and impede the development of tumors in in vivo models. Since they are functionally dependent on the SWI/SNF complex, they will inevitably be negatively impacted when either BRM or BRG1 are lost during tumor development. Thus, we hypothesize that alterations to the SWI/SNF complex not only occur in NSCL cancer but also likely underlie and contribute to the develop of BACs. Mechanistically, this will promote cancer development by inactivating regulatory pathways dependent on the SWI/SNF complex, including RAR. To understand the potential role of the SWI/SNF complex in the genesis of BAC, we have proposed to immunostain our BAC tissue microarray consisting of 150 pathological verified cases and determine if BRG1, BRM or other SWI/SNF subunits are lost. Additionally, we have proposed to discover the mechanism of their abrogation by sequencing these genes. To clarify how these potential changes strip the cell of its growth control mechanism, thereby allowing the development of BAC, we specifically focus on examining the effects of BRM loss on the antitumorigenic effects of retinoids using an established animal model. These studies are not only important because they provide much need tools for the study of BAC, but also because they help define novel molecular change, which could assist the development of relevant clinically targeted therapies. Finally, these studies have the potential to explain why retinoids have not been found to have chemopreventive effects in lung cancer.