Potential Marker of Aging, Breast Cancer Risk Discovered 

As we age, we may turn down the volume on our music and dial down the number of late nights, but deep inside our bodies, expression levels of a gene called midkine are ratcheting upward. This uptick appears to have impact on our health. 

New work from the Dana-Farber lab of breast cancer researcher Kornelia Polyak, MD, PhD, has found that as levels of midkine increase, so does the likelihood of breast cancer in animal studies. According to the study, levels of midkine also increase in humans with age and are elevated in multiple forms of human cancer.  

The findings, which could lead to possible strategies for lowering the risk of breast cancer, were published in Cancer Cell. 

“Midkine very clearly goes up with age and is actually increased in many of the human cancers,” says Polyak. “It could be a marker of age – your biological age – and a marker of increased risk of cancer.”  

Age has long been a known risk factor for breast cancer. Older people are more likely to develop breast cancer, with the median age of diagnosis in the US being 62.  

Connection to humans 

In humans, midkine has been linked to neurological and inflammatory diseases. To learn more about its connection to human cancers, Polyak’s team looked at samples of breast tissue from human patients and found higher levels of midkine in those with breast cancer. In addition, the team analyzed data from the Cancer Genome Atlas and found elevated midkine expression levels in 24 out of 31 tumor types, including breast cancer.  

Polyak and her team are following up on these findings with a study of patients with breast cancer to learn more. 

“We would like to see if midkine could be a marker for breast cancer risk, or maybe cancer risk in general,” says Polyak. 

The team also found that midkine is sometimes upregulated in younger patients. In young patients with estrogen-receptor-positive (ER+) breast cancer, for example, they found that elevated midkine in tumor cells could predict a poor prognosis. Further, in young people who do not have breast cancer, midkine was more likely to be elevated in those who had other known risk factors for developing breast cancer. 

Connection to cancer 

To learn more about what midkine does in the body, Polyak’s team studied it in animals. Initially, they noted changes with age in cells in the mammary glands. The changes were precancerous. Specifically, they found an increase in a population of cells called luminal progenitor cells, which are cells that normally would differentiate into mature cells in the breast but instead get stuck in state of limbo. In this immature state, they are more likely to replicate rapidly, which is a feature of cancer.  

Deep analyses of these individual cells led the team to identify midkine as a key factor initiating these changes. They found that not only is midkine activity significantly upregulated in these luminal progenitor cells, but also it activates a known pathway related to the development of cancer, the PI3K/AKT signaling pathway.  

Further, the team found a drop in the number of immune cells surrounding these cells, suggesting that midkine could influence the tumor microenvironment, making it less capable of detecting and destroying precancerous cells. 

These observations suggest that an uptick in midkine expression increases the chances of cancer. Further research showed that artificially elevated levels of midkine in young animals resulted in similar precancerous changes and an increased risk of cancer.  

“Midkine seems to be driving these changes with age in the breast,” says Polyak.  

Toward clinical utility 

Polyak is eager to validate midkine as a cancer risk factor because it could have clinical value. For example, she envisions that a simple blood test could be offered to young people to evaluate midkine levels. Those with elevated levels could be directed to start mammograms at an earlier age than current clinical guidelines recommend. Earlier screening could help diagnose cases of breast cancer early and improve survival. 

“One of the problems with breast cancer in younger people is that they are frequently diagnosed at a more advanced stage because young people do not get regular mammograms,” says Polyak.  

In addition, Polyak would like to determine if there are ways to interfere with midkine to stave off cancer. There aren’t any specific midkine inhibitors, so it currently isn’t possible to test whether interfering with it could reduce the risk of cancer. However, an alternate approach is to target the cells that are producing midkine, potentially with a vaccine. 

About the Medical Reviewer

Kornelia Polyak, MD, PhD, is a Professor of Medicine at Dana-Farber Cancer Institute, Harvard Medical School, and a co-leader of the Dana-Farber Harvard Cancer Center Cancer Cell Biology Program.  Dr. Polyak is an internationally recognized leader of breast cancer research.  Her laboratory is dedicated to improving the clinical management of breast cancer patients by understanding molecular and cellular determinants of breast cancer risk and tumor evolution.  Dr. Polyak has devoted much effort to develop new ways to study tumors and to apply interdisciplinary approaches.  Dr. Polyak has received numerous awards including the Paul Marks Prize for Cancer Research, AACR Outstanding Investigator Award for Breast Cancer Research, and the 14th Rosalind E. Franklin Award for Women in Science.  She is a recipient of the NCI Outstanding Investigator award (2015 and 2022) and received a Distinguished Alumna Award from Weil-Cornell in 2020.  Dr. Polyak was the American Association for the Advancement of Science Fellow in 2019, member of the Fellows of the AACR Academy in 2020, and to the National Academy of Sciences and the National Academy of Medicine in 2022.  She was also a recipient of the American Cancer Society Research Professor Award in 2022 and received the 2023 AAACR Distinguished Lectureship in Breast Cancer Research award.