Vanderbilt researchers find proteins may point way to new prostate cancer drug targets

August 06, 2012

Two proteins that act in opposing directions - one that promotes cancer and one that suppresses cancer -- regulate the same set of genes in prostate cancer, Vanderbilt-Ingram Cancer Center researchers have found.

The findings, reported recently in the Journal of Clinical Investigation, point toward potential drug targets and prognostic markers for prostate cancer.

"We are trying to understand the molecular genetics of prostate cancer: what are the genes that are altered in human prostate cancer, and very importantly, how do they lead to cancer when they are changed?" said Sarki Abdulkadir, M.D., Ph.D., associate professor of Pathology, Microbiology and Immunology and of Cancer Biology.

Abdulkadir's lab uses mouse models to probe the molecular pathways involved in prostate cancer.

Two separate projects in the lab unexpectedly came together for this study -- one led by postdoctoral fellow Philip Anderson, Ph.D., and the other spearheaded by (then) graduate student Sydika McKissic, Ph.D.

Anderson was using genomic approaches to understand how loss of a tumor suppressor protein, called NKX3.1, promotes prostate cancer. NKX3.1 is a transcription factor, meaning that it binds to and regulates the expression of other genes, turning them "on" or "off."

"It is one of the genes most commonly deleted in human prostate cancer...and is lost very early," explained Abdulkadir.

Anderson isolated the NKX3.1 protein and identified a set of 9,817 genes that bind to the protein. Of that set, he identified 282 genes that are regulated by the protein - i.e., their expression was altered by loss of NKX3.1.

"So we took those genes...and asked 'what is interesting about these genes?'" said Abdulkadir.

Using bioinformatics tools, the investigators found a quarter of the NKX3.1-regulated genes are also bound by a "famous" oncogene called Myc (which, like NKX3.1, is also a transcription factor).

It was previously known that, as human prostate cancer progresses, NKX3.1 levels decrease and Myc levels increase. The research team's findings showed that these two proteins with opposing functions regulated a similar set of genes.

"What we showed in this paper is that actually in many instances, NKX binds and represses these genes while Myc binds and activates them," Abdulkadir said. "The way we think about it is this: Myc is the 'accelerator' and NKX3.1 is the 'brake' (on cancer growth)."

Meanwhile, McKissic was working to develop a mouse model of prostate cancer. However, mice lacking NKX3.1 alone developed early stage prostate cancer, but the disease would not progress. Abdulkadir suspected that another genetic "hit" or mutation was necessary to progress fully to prostate cancer and suspected that Myc was a good candidate for that second "hit" based on how commonly the gene is altered in human prostate cancer.

So McKissic developed a mouse model in which NKX3.1 was deleted and Myc was overexpressed in the specific prostate cells where cancer arises.

She showed that mice with this combination of genetic alterations did progress to advanced cancer -- and that the same target genes identified in Anderson's project were dysregulated in the mouse model.

To determine clinical relevance, the researchers then analyzed genetic and clinical data from patients with prostate cancer. They found that expression of these target genes was associated with tumor relapse - specifically, that suppression of a subset of the target genes may predict relapse.

In addition to potential prognostic indicators of relapse, these "cross-regulated" genes may present therapeutic targets to halt progression of prostate cancer.

Future studies on the roles of the individual target genes could help reveal "which of these genes are bigger players than others for things like therapeutics," Abdulkadir said.
-end-
The research was supported by grants from the National Cancer Institute (CA094858, CA123484, CA148950, and CA126505) of the National Institute of Health and from the Department of Defense.

Vanderbilt University Medical Center

Related Prostate Cancer Articles from Brightsurf:

Low risk of cancer spread on active surveillance for early prostate cancer
Men undergoing active surveillance for prostate cancer have very low rates - one percent or less - of cancer spread (metastases) or death from prostate cancer, according to a recent study published in the Journal of Urology®, an Official Journal of the American Urological Association (AUA).

ESMO 2020: Breast cancer drug set to transform prostate cancer treatment
A drug used to treat breast and ovarian cancer can extend the lives of some men with prostate cancer and should become a new standard treatment for the disease, concludes a major trial which is set to change clinical practice.

Major trial shows breast cancer drug can hit prostate cancer Achilles heel
A drug already licensed for the treatment of breast and ovarian cancers is more effective than targeted hormone therapy at keeping cancer in check in some men with advanced prostate cancer, a major clinical trial reports.

The Lancet: Prostate cancer study finds molecular imaging could transform management of patients with aggressive cancer
Results from a randomised controlled trial involving 300 prostate cancer patients find that a molecular imaging technique is more accurate than conventional medical imaging and recommends the scans be introduced into routine clinical practice.

Common genetic defect in prostate cancer inspires path to new anti-cancer drugs
Researchers found that, in prostate cancer, a mutation leading to the loss of one allele of a tumor suppressor gene known as PPP2R2A is enough to worsen a tumor caused by other mutations.

First prostate cancer therapy to target genes delays cancer progression
For the first time, prostate cancer has been treated based on the genetic makeup of the cancer, resulting in delayed disease progression, delayed time to pain progression, and potentially extending lives in patients with advanced, metastatic prostate cancer, reports a large phase 3 trial.

Men taking medications for enlarged prostate face delays in prostate cancer diagnosis
University of California San Diego School of Medicine researchers report that men treated with medications for benign prostatic hyperplasia (enlarged prostate) experienced a two-year delay in diagnosis of their prostate cancer and were twice as likely to have advanced disease upon diagnosis.

CNIO researchers confirm links between aggressive prostate cancer and hereditary breast cancer
The study has potential implications for families with members suffering from these types of tumours who are at an increased risk of developing cancer.

Distinguishing fatal prostate cancer from 'manageable' cancer now possible
Scientists at the University of York have found a way of distinguishing between fatal prostate cancer and manageable cancer, which could reduce unnecessary surgeries and radiotherapy.

Researchers find prostate cancer drug byproduct can fuel cancer cells
A genetic anomaly in certain men with prostate cancer may impact their response to common drugs used to treat the disease, according to new research at Cleveland Clinic.

Read More: Prostate Cancer News and Prostate Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.