Random DNA mix-ups not so random in cancer development

December 03, 2009

Researchers at the UC San Diego School of Medicine have pinpointed a mechanism that may help explain how chromosomal translocations - the supposedly random shuffling of large chunks of DNA that frequently lead to cancer - aren't so random after all. They have developed a model of such chromosomal mix-ups in prostate cancer which indicates that the male sex hormone (androgen) receptor unexpectedly plays a key role in driving specific translocations in the development of cancer.

A better understanding of the origin and behavior of such translocations may ultimately lead to ways to both predict and perhaps interfere with their formation, and in turn, cancer development.

Chunru (Ruth) Lin, Liuqing (Luke) Yang and Michael G. Rosenfeld, MD, Howard Hughes Medical Institute investigator and Professor of Medicine at the UC San Diego School of Medicine, headed the basic research study, to be published on line December 3, 2009 in advance of publication in the journal Cell.

A series of studies showed that, under certain conditions involving some sort of genetic "stress" - such as cigarette smoke, a toxic chemical exposure or radiation - the androgen receptor can act in concert with several key enzymes and pathways induced by genotoxic stress to unexpectedly direct specific translocations leading to cancer.

"In the future, one goal would be to find tumor-causing translocations in breast and other cancers and develop a chemical library screen to find compounds that might inhibit these events in cancer formation/behavior," said Rosenfeld.

According to Rosenfeld, chromosome mix-ups are a hallmark of leukemias and lymphomas and, increasingly, other cancers such as more aggressive forms of prostate cancer. Scientists have known that various types of genetic stress can lead to random breaks in DNA and rearrangements in chromosomes, resulting in excessive cell growth and cancer, but the exact mechanisms have been poorly understood.

Evidence from other research teams pointed to the important role of the androgen receptor in the development of translocations in more aggressive forms of prostate cancer. The UC San Diego research team created a tumor translocation model in prostate cancer and found that instead of random DNA breaks, the breaks were in specific chromosomal areas bound by the androgen receptor which directed the pattern of cancer-causing translocations.

Rosenfeld's group identified several mechanisms, some involving specific enzymatic pathways that worked together with the androgen receptor to form specific translocations.

"Our findings suggest that sex steroid receptors - androgen and estrogen receptors - can cause mutations when in the presence of genotoxic stress, and form site-specific chromosomal translocations," Rosenfeld said.

He noted that understanding the molecular mechanisms that underlie tumor translocations and the specific strategies used by normal cells to protect against such rearrangements could provide insights into cancer development and eventually help in the development of new therapeutic approaches.
-end-
Additional contributors include co-first authors Chunru Lin and Liuqing Yang, Bogdan Tanasa, Kenny Ohgi and Jie Zhang of the Howard Hughes Medical Institute (HHMI); Bong-gun Ju, HHMI and Sogang University, Seoul; Kasey Hutt, UCSD Bioinformatics Graduate Program; Dave Rose, UCSD Department of Medicine, Division of Endocrinology and Metabolism; and Xiang-Dong Fu and Christopher K. Glass, UCSD Department of Cellular and Molecular Medicine.

This study was funded in part by grants from The National Institutes of Health/National Cancer Institute, the Department of Defense and the Prostate Cancer Foundation.

University of California - San Diego

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.