What this means for patients: Obesity is a known risk factor for prostate cancer, but the reasons for this remain unknown. This study identifies expression of chromatin remodeling genes as a likely mechanism linking these processes, and may lead to the development of therapies for obesity-related prostate cancer.

June 2, 2015 — Obesity is known to increase the risk for prostate cancer, particularly for high-risk, lethal disease. This risk is further increased in African American men. A number of molecular mechanisms may be involved in the relationship between obesity and lethal prostate cancer including the production of tumor-promoting growth factors and metabolites by adipose cells and the accompaniment of obesity by inflammation which can abrogate the normal functions of the immune system. However, much work needs to be done to understand the cause and effect relationships between these complex biologies.

Ericka Ebot, PhD, MPH

The combination of epidemiology and molecular pathology is a powerful research methodology for identifying connections between epidemiologic measurements such as diet or lifestyle, and molecular mechanisms that contribute to disease. At the 2015 Annual AACR Meeting, held from April 18-22 in Philadelphia, PA, Dr. Ericka Ebot, of the Harvard T.H. Chan School of Public Health, presented data that implicates another molecular mechanism – chromatin remodeling –in the links between obesity and prostate cancer.

Ebot conducted a study on 402 prostate cancer patients diagnosed between 1982 and 2005 and for whom both archival tumor tissue and an average of 13-years of follow-up data on patient outcome were available. The study included 113 men who progressed to lethal prostate cancer and 289 men who had indolent cancers (defined as follow-up without evidence of metastatic disease). All of these men were participants in the Health Professionals Follow-up Study or the Physicians’ Health Study, two long-term Harvard studies that include periodic surveys to follow the lifestyle and health of participants. These surveys were used to determine self-reported BMI values prior to the diagnosis of prostate cancer. Tumor tissues and adjacent normal prostate tissues obtained during the patients’ original radical prostatectomy surgeries were evaluated by whole genome transcriptome sequencing to determine gene expression levels. The top molecular pathways that were most highly expressed in the prostate tumors of obese men (BMI >27.5 kg/m²) vs. men of a healthy BMI (18.5 to 25 kg/m²) were involved in the process of chromatin remodeling. In addition, higher expression of the chromatin remodeling genes was associated with more advanced tumor stage, higher Gleason grade, and also a 5 times greater risk of lethal progression (even beyond associations with the clinical features).

Chromatin remodeling is a major mechanism regulating gene expression. In this process, the regions of chromosomal DNA surrounding a gene are modified by the additions and subtractions of various molecules that cause the DNA to alter its structure and become accessible or inaccessible for transcription factors to attach and transcribe the gene into RNA. This “epigenetic” process is heritable as a cell divides and is the primary mechanism by which the identity and functions of a cell are passed from parent to daughter when a cell divides. While tumor cells are normally thought to pass their dysfunctional state to their offspring via genetic mutations, epigenetic processes have also been shown to be important in maintaining many oncogenic activities of tumor cells. This study therefore implicates obesity in affecting epigenetic processes that promote the development of high risk and lethal prostate cancer. Future studies will aim at understanding the connections between these mechanisms in more detail and could lead to the development of new preventative measures or treatments strategies for prostate cancer.

Dr. Ebot is a postdoctoral fellow in the lab of Dr. Lorelei Mucci, a Prostate Cancer Foundation Young Investigator from 2008-2011. This study was also partially funded by a Prostate Cancer Foundation Challenge Award (PIs Loda and Mucci) as well as the Dana-Farber/Harvard Cancer Center SPORE in Prostate Cancer.

Dr. Andrea Miyahira has a PhD in cancer immunology, and is Manager of Scientific Programs at the Prostate Cancer Foundation.