Marino N, et al., 2022

Breast cancer is still one of the main causes of cancer-related death in women. Scientists have made progress in finding risk factors—like age, family history, and certain inherited gene changes—but these don’t fully explain why some women get breast cancer and others don’t. Because of this, many women are labeled as “high-risk” based on models that estimate future cancer risk. But researchers still don’t fully understand what’s happening inside the breast at the molecular level before cancer develops.

To prevent breast cancer or catch it earlier, researchers want to better understand the earliest biological changes that occur in healthy breast tissue, especially in women who are at high risk. However, most past studies have focused on tissue collected after cancer is diagnosed, which may not reflect the state of the breast before disease begins. What’s missing is a clear understanding of what normal breast tissue looks like—and how it might quietly change in ways that lead to cancer later.

This study set out to answer a key question: Are there molecular differences in the breast tissue of healthy women who are at higher risk of breast cancer?

Full-Text Journal Article PubMed

What did they study?

Researchers collected breast tissue from 146 healthy women who voluntarily donated samples to the Komen Tissue Bank. These women were divided into two groups: those deemed at high risk and those at average risk for developing breast cancer, based on a widely used risk score. The researchers then studied the samples using two main techniques:

1. Gene activity analysis: The researchers studied which genes were more or less active in the breast tissue. This helps show what the cells are doing and whether certain processes linked to cancer are starting to happen.
2. DNA methylation profiling: They also studied a process called DNA methylation. This is a molecular tag that works like placing sticky notes on certain genes to control how much they’re used. These changes don’t affect the DNA itself but can influence how cells function. Abnormal methylation can contribute to cancer.

   They also studied a smaller group of women who donated tissue at two different time points. This allowed them to look at how aging affects these molecular patterns and whether any changes were more pronounced in high-risk women.

What did they find?

1. DNA methylation patterns were different in high-risk tissue. The team found nearly 1,700 spots in the genome where methylation patterns were different in high-risk tissue. Most of these changes involved patterns where parts of the DNA had more of these tags than expected. These changes mostly occurred in regions of the DNA that help regulate genes.
2. There was only a weak link between changes in DNA methylation and changes in gene activity. When scientists looked at gene activity and methylation in the same tissue samples, they found only a weak connection between the two. This means that methylation alone doesn't explain all the differences in how genes behave in high-risk breast tissue.
3. As women aged, certain molecular changes were more pronounced in those at high risk. For women who gave breast tissue at two different times, the study found that some molecular changes increased with age—and these changes were more extreme in high-risk women. For example, five genes changed more with age in high-risk tissue. Two of these genes also showed signs that their activity may be influenced by DNA methylation.
4. Some age-related DNA changes in high-risk women resembled known cancer patterns. Although the overlap wasn’t huge, a small portion of the methylation changes in high-risk breast tissue matched known patterns seen in breast cancer. This hints that some of the early steps toward cancer may already be happening in these women’s normal-looking tissue.

Why is this study important?

Finally, the study also underscores that breast tissue changes with age, and in high-risk women, those changes may be more dramatic. This supports the idea that age and risk status together affect how breast tissue behaves over time.

Full citation

Marino N,German R,Podicheti R,Rusch DB,Rockey P,Huang J,Sandusky GE,Temm CJ,Althouse S,Nephew KP,Nakshatri H,Liu J,Vode A,Cao S,Storniolo AMV Aberrant epigenetic and transcriptional events associated with breast cancer risk.. Clinical epigenetics 2022 Feb; 14 (1). PMID:35139887.