Breast cancer could be prevented by targeting epigenetic proteins, study suggests

June 19, 2018, Rockefeller University Press
The epigenetic regulatory protein DNA methyltransferase 1 (green) is highly expressed in the luminal cells of mammary gland ducts (compared with basal cells, red). Treatment with the inhibitor decitabine (right) prevents luminal cell progenitors from expanding this population of cells in response to progesterone. Credit: Casey et al., 2018

Researchers at the Princess Margaret Cancer Centre in Toronto have discovered that epigenetic proteins promote the proliferation of mammary gland stem cells in response to the sex hormone progesterone. The study, which will be published June 19 in the Journal of Cell Biology, suggests that inhibiting these proteins with drugs could prevent the development of breast cancer in women at high risk of the disease.

Mammary glands contain two types of , basal and luminal, that arise from specialized stem or cells. During pregnancy or the menstrual cycle, progesterone induces basal and luminal progenitor cell numbers to expand and drive mammary formation. But mammary gland progenitors may also give rise to . Progesterone exposure and stem cell proliferation have been linked to the development of , and the number of progenitor cells is often elevated in women carrying mutations in BRCA1 or other genes that put them at a high risk of developing the disease.

"Currently, there are no standard of care preventative interventions for women at high risk of breast cancer," says Dr. Rama Khokha, a Senior Scientist at Princess Margaret Cancer Centre and Professor of Medical Biophysics at the University of Toronto. "Although it is becoming increasingly clear that stem and progenitor cells underlie cancer development, we lack strategies to target these cells for chemoprevention."

To learn more about these progenitor cells and identify any vulnerabilities that could potentially be exploited to prevent the development of breast cancer, Khokha and colleagues isolated cells from the mammary glands of mice and examined how they changed in response to progesterone. The researchers had previously measured all of the RNA molecules produced by mammary gland cells. Now they quantified all of the cells' proteins and assessed the cells' epigenomes—the various chemical modifications to a cell's chromosomes that help determine which genes are turned on and off.

This global overview of mammary gland cells revealed that in response to progesterone, progenitor cells—particularly luminal progenitor cells—up-regulate many of the epigenetic regulatory proteins responsible for modifying the cells' chromosomes.

"We thought that drugs that inhibit these epigenetic regulatory proteins might suppress the proliferation of stem and progenitor cells in response to progesterone," Khokha says.

The researchers tested multiple epigenetic inhibitors, many of which are already approved for use in humans by the FDA. Several of these drugs inhibited the proliferation of mammary gland progenitor cells and decreased their total number in mice. One, a drug called decitabine that inhibits DNA methyltransferase enzymes and is approved to treat myelodysplastic syndrome, delayed the formation of tumors in breast cancer-prone rodents.

Khokha and colleagues then tested the effects of epigenetic inhibitors on progenitor cells isolated from women at high risk of developing breast cancer. Progenitor cells from patients with BRCA1 mutations were particularly vulnerable to epigenetic inhibitors, including decitabine. Decitabine also suppressed the activity of progenitor cells from patients with mutations in the BRCA2 gene.

"This demonstrates that the dependency of on specific epigenetic proteins is conserved between mice and humans and highlights the potential of epigenetic therapies to target these important cell types in the human breast as a form of chemoprevention," says Khokha.

Explore further: Cells of origin for breast tumours identified

More information: Casey et al., Journal of Cell Biology (2018). DOI: 10.1083/jcb.201804042

Related Stories

Cells of origin for breast tumours identified

November 2, 2016
Breast cancer is the most common cancer type in women in Sweden and worldwide. It has long been known that not all breast cancers are similar: Luminal tumours consist mostly of cells that are similar to those found in the ...

Researchers identify oestrogen receptor stem cells in the mammary gland.

August 16, 2017
One of the key questions in stem cell and cancer biology is to understand the cellular hierarchy governing tissue development and maintenance and the cancer cell of origin. In a study published in Cell Reports, researchers ...

Scientists identify progenitor cells, potential new 'roots' of breast cancer

October 29, 2012
Scientists have discovered new types of early cells in mammary glands, uncovering clues to the origins of different breast cancers - and potential new drug targets, according to findings published in Breast Cancer Research.

Changes in progenitor cell population in breast may be overlooked factor in breast cancer

December 17, 2012
The DNA mutations that accumulate over time as women age are not the sole contributor to the higher frequency of breast cancer in women over 50, Mark LaBarge, PhD, a researcher at Lawrence Berkeley National Laboratory (LBNL) ...

Recommended for you

Scientists sharpen the edges of cancer chemotherapy with CRISPR

July 13, 2018
Tackling unsolved problems is a cornerstone of scientific research, propelled by the power and promise of new technologies. Indeed, one of the shiniest tools in the biomedical toolkit these days is the genome editing system ...

Looking at the urine and blood may be best in diagnosing myeloma

July 13, 2018
When it comes to diagnosing a condition in which the plasma cells that normally make antibodies to protect us instead become cancerous, it may be better to look at the urine as well as the serum of our blood for answers, ...

Massive genome havoc in breast cancer is revealed

July 12, 2018
In cancer cells, genetic errors wreak havoc. Misspelled genes, as well as structural variations—larger-scale rearrangements of DNA that can encompass large chunks of chromosomes—disturb carefully balanced mechanisms that ...

Study shows biomarker panel boosts lung cancer risk assessment for smokers

July 12, 2018
A four-protein biomarker blood test improves lung cancer risk assessment over existing guidelines that rely solely upon smoking history, capturing risk for people who have ever smoked, not only for heavy smokers, an international ...

Discovering the mechanisms that underlie prostate cancer

July 12, 2018
New research has uncovered insights into the mechanisms that underlie prostate cancer, providing potential targets for new cancer therapies.

New method reveals how well cancer drugs hit their targets

July 12, 2018
Scientists have developed a technique that allows them to measure how well cancer drugs reach their targets inside the body. It shows individual cancer cells in a tumour in real time, revealing which cells interact with the ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.