Healthy epithelial cells in breast tissue secrete an anticancer protein called interleukin 25 (IL25) that instructs malignant cells to self-destruct, leaving healthy cells intact, according to new research from the US published online this week in the journal Science Translational Medicine. The researchers hope their discovery provides a new target for drug development.

IL25 is already known for its role in the immune system’s response to inflammation.

Lead researcher and corresponding author, Dr Mina Bissell, a breast cancer authority at the US Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) in California, told the media that:

“We found that normal breast cells provide an innate defense mechanism against cancer by producing interleukin 25 (IL25) to actively and specifically kill breast cancer cells.”

“This suggests that IL25 receptor signaling may provide a new therapeutic target for the treatment of breast cancer,” she added.

The researchers wrote in their background information that we already know that as cells differentiate into tissue, the microenvironment that surrounds them must be well organized to ensure healthy growth and maintenance.

So Bissell and colleagues from the University of California, Irvine, wondered if this organization included producing substances to thwart the emergence of malignant cells in and near healthy tissue.

In their paper they describe how they identified six factors secreted by healthy “mammary epithelial cells (MECs) differentiating in three-dimensional laminin-rich gels” that have a toxic effect on breast cancer cells. Of those six, IL25 had the highest anticancer effect without affecting normal mammary epithelial cells.

Given the exposure that humans have every day to radiation and chemical damage, plus other things that can damage DNA, the rate of cancer is surprisingly low, even though it is a leading cause of premature death in the world.

It is not as though mutant cells aren’t being generated, said lead author, Dr Saori Furuta, a molecular biologist and Berkeley Lab colleague of Bissell’s.

Our bodies produce about 1,000 genetically impaired cells every day, but our tumor-surveillance systems get rid of them, as part of the finely balanced homeostatic process. Previous studies have described a number of tumor surveillance mechanisms, including tumor suppressors, immune surveillance and rogue cell suppression by various mechanisms in the matrix that surrounds cells.

Furuta said:

“We are now adding a new type of tumor suppression to this list, IL25 and other proteins secreted by normal breast cells that kill or subdue their mutated neighbors.”

The researchers discovered that the reason IL25 was toxic to cancerour breast cells but not to normal breast cells was because there was an abundance of IL25 receptors on the cancerous cells but not on the normal cells. This means IL25 was able to enter the malignant cells and trigger their self-destruct mechanism (apoptosis).

“Since IL25 is produced by healthy breast tissue as a natural defense mechanism against cancer during the cell differentiation process, we should be able to utilize IL25/IL25 receptor signaling as an organic approach to breast cancer therapy,” explained Furuta.

One of the ways that normal cells work with their microenvironment to maintain tissue health and integrity is by secreting cell signalling proteins that promote healthy cells and inhibit abnormal cells.

In previous studies, Furuta and colleagues found that some material extracted from normal mammary epithelial cells while they were in a particular stage of growth in a 3D lab culture could induce cancerous breast cancer cells to “revert” and behave like normal cells. They also found similar results when they used certain cell signalling inhibitors.

They then used various techniques to narrow down to IL25.

Using a technique called “fractionating” for solubility and size, they found that the most potent tumor cell-killing activity took place in the molecular size range equivalent to a protein. Using mass spectrometry they identified the cytokine IL25 as the most potent cell-killing protein. And then using functional assays they found IL25 interacts with the IL25 receptor to trigger apoptosis or cell death.

“We analyzed randomized cohorts of breast biopsy samples and found that 20-percent of the breast cancer samples tested were IL25 receptor-positive” said Furuta.

“Importantly, these IL25 receptor-positive tumors were highly invasive and correlated to poor clinical outcome patients. We believe that in the future the IL25 receptor will serve as a novel therapeutic marker for breast cancer diagnosis and treatment,” she added.

The team is now investigating five other proteins they found being secreted by normal breast cells. These stop the growth of cancer cells rather that kill them, but they could still have potential for developing combined drug treatments for aggressive breast and other cancers.

Most of the funding for the study came from the National Institutes of Health’s National Cancer Institute.

“IL-25 Causes Apoptosis of IL-25R-Expressing Breast Cancer Cells Without Toxicity to Nonmalignant Cells.”
Saori Furuta, Yung-Ming Jeng, Longen Zhou, Lan Huang, Irene Kuhn, Mina J. Bissell, Wen-Hwa Lee.
Sci Transl Med 13 April 2011: Vol. 3, Issue 78, p. 78ra31
DOI: 10.1126/scitranslmed.3001374

Additional sources: Berkeley Lab (news release, 13 Apr 2011).

Written by: Catharine Paddock, PhD