Subtle changes in normal genes implicated in breast cancer

July 13, 2005

BOSTON--Using a super-efficient method they invented to search for a type of cancer-related change in all genes of a cell, Dana-Farber Cancer Institute researchers have discovered new evidence about how the "microenvironment" of breast cancers helps drive the cancers' growth and migration.

The scientists found that non-cancerous cells surrounding young breast cancers -- the microenvironment -- undergo epigenetic modifications. (Epigenetic modifications affect genetic function and are passed along to the cell's offspring, but they don't alter a gene's actual structure or DNA.) The subtly altered gene function causes the microenvironment cells to send signals to the breast tumor cells to grow fast and become more aggressive.

"This is the first demonstration that epigenetic occur in the supportive cells of a tumor, and this further emphasizes that surrounding cells play an active role in cancer formation and growth," says Kornelia Polyak, MD, PhD. "These changes in the microenvironment may occur before breast duct cells undergo genetic changes that cause cancer, thus detecting the epigenetic alterations may be a means of early cancer diagnosis or even predicting cancer risk."

Polyak is senior author of the paper, which was posted this week as an advance online publication on the Nature Genetics web site, http://www.nature.com/ng. The first author of the paper is Min Hu, PhD, of Dana-Farber.

Polyak and her colleagues had previously shown that the genes in the microenvironment surrounding the breast's milk ducts were overactive, and that they continued to be overactive when their cells reproduced, even though their DNA had not been altered. She suspected that the methylation state of the cells' DNA was being inherited. A gene's activity can be regulated by a kind of chemical switch process, methylation, when units called methyl groups are added or removed from the gene's DNA. The on-off pattern of methylation in a cell's genes can be passed from one generation to another, even when the DNA remains unchanged. This is an example of an epigenetic modification.

Cancer is often associated with less-than-normal methylation of cells' DNA. Techniques exist for checking the methylation state of a cell, gene by gene. But Polyak and her colleagues, looking to obtain the methylation pattern of a cell's entire genome (approximately 20,000-25,000 genes) at once, devised a method called Methylation Specific Digital Karyotyping (MSDK) that can read a cell's complete methylation profile. Polyak and her colleague obtained a profile of the entire genome in a few weeks, a task that would have taken several weeks to months, if it was even possible, using conventional methods.

Using MSDK to study breast cancer tissue, the scientists tested the epithelial and myoepithelial cells that line the breast ducts, and the surrounding cells, known as stoma, including fibroblasts. They found that in all of these cell types, gene expression was altered by epigenetic methylation changes that were not present in normal breast tissue cells.

Most breast cancers develop in the inner lining of the breast's milk ducts. Some cancerous lesions remain confined within the ducts for years -- called ductal carcinoma in situ or DCIS. Others become invasive, breaking through the walls of the duct into the breast tissue, and threatening to metastasize throughout the body. In previous work, the Dana-Farber scientists showed that the stromal cells of the microenvironment, while not malignant themselves, can goad the cancer cells within the duct into more aggressive action. This insight, the researchers commented, provide a rationale for future chemotherapy that targets the stromal cells as well as the tumors themselves.

In addition to furthering scientific understanding of how breast cancers grow, the method and the new findings could aid in the discovery of biomarkers, or physical changes that could be used in the early detection of breast cancers before they can be diagnosed by conventional means.

Polyak said that Dana-Farber has filed for a patent on the method and the genes identified as aberrantly methylated in the various cell types, and is working with a company to use it for the development of diagnostic tools for early breast cancer diagnosis.
-end-
In addition to Polyak and Hu, the paper's other authors are Jun Yao, PhD, and Li Cai, MD, PhD, Dana-Farber; Kurt E. Bachman, PhD, University of Maryland; Frederic van den Brule, MD, PhD, University of Liege, Belgium; and Victor Velculescu, MD, PhD, Johns Hopkins University.

The research was supported by a SPORE grant from the National Cancer Institute to the Dana-Farber/Harvard Cancer Center, and grants from the Department of Defense and the American Cancer Society.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.

Dana-Farber Cancer Institute

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and 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.