In breast cancer research, one of the most important questions we ask is not just how tumors grow but what type of cells they come from. Breast cancers are not all the same. They are classified into different subtypes based on the characteristics of the cells they resemble. Some tumors look like luminal cells, which are the cells lining the milk ducts and often express hormone receptors like estrogen receptor (ER). Others resemble basal cells, which are deeper in the tissue and tend to be more aggressive and harder to treat.
This distinction between luminal and basal is more than just a label. It determines how a tumor behaves, how it responds to treatment, and ultimately, how likely it is to come back. Understanding what controls this cellular identity is critical for designing more effective therapies and helping patients live longer and better lives.
The Epigenetic Code Behind Cell Fate
While much of cancer research focuses on mutations in DNA, we now know that epigenetic changes play an equally powerful role. Epigenetics refers to chemical modifications that turn genes on or off without changing the DNA sequence itself. One of the most important of these modifications is DNA methylation, which acts like a switch. When a gene is highly methylated, it usually gets turned off. When methylation is removed, the gene can be turned back on.
In our recent research at China Medical University, we discovered that epigenetic regulation helps control whether a breast cell becomes a luminal cell or a basal-like cell, and this regulation is especially relevant in the development of hormone receptor-positive breast cancer.
The Role of TET2 in Cell Differentiation
Our work focused on a gene called TET2, which helps remove DNA methylation and therefore supports the activation of key genes that drive luminal cell identity. TET2 plays the role of an epigenetic editor. It removes the chemical tags that silence important genes and allows the cell to become what it was meant to be.
In our mouse models, when we deleted TET2 in mammary epithelial cells, the result was dramatic. The cells failed to express key luminal markers like ESR1, the gene that produces the estrogen receptor, along with GATA3 and FOXA1. Without TET2, the cells began to shift away from a luminal fate and started developing into basal-like tumors, which are typically ER-negative and much more difficult to treat.
This shift was not caused by a mutation in ESR1 or other genes. Instead, the machinery that normally keeps these genes active was no longer functioning, all because TET2 was missing. This finding gave us a powerful insight into how the loss of epigenetic regulation can push cells in a completely different direction.
The FOXP1 Connection
We also found that TET2 does not work alone. It partners with another molecule called FOXP1, a transcription factor that binds to specific regions of DNA and helps regulate gene expression. Together, TET2 and FOXP1 form a molecular complex that activates the genes necessary for luminal identity.
When this partnership breaks down, the consequences are serious. Without FOXP1 or TET2, the genes that support luminal cell development cannot be properly activated. The cells lose their identity and the resulting tumors behave more like basal cells. These tumors do not respond to hormone therapy and often carry a worse prognosis.
This mechanism helped us better understand a frustrating clinical problem. Some patients with ER-positive breast cancer begin treatment with tamoxifen or aromatase inhibitors but eventually relapse with tumors that no longer express ER. It turns out that in some cases, this may be linked to the epigenetic silencing of ESR1, driven by the loss of TET2.
What This Means for Treatment
Understanding the molecular switches that control cell fate gives us new tools for developing better therapies. If a tumor has lost TET2 function and become resistant to endocrine therapy, we may be able to reactivate those pathways by targeting the epigenetic changes directly.
There are already drugs being tested that affect DNA methylation. Some of these are used in blood cancers and may hold promise in solid tumors like breast cancer. By restoring TET2 activity or mimicking its effects, we could potentially reprogram basal-like tumors to behave more like luminal tumors, making them sensitive to hormone therapy once again.
Another possibility is using TET2 expression as a biomarker. If we know a patient’s tumor has low TET2, we can predict that hormone therapy may not be effective and consider alternative or combination treatments from the beginning. This is the kind of personalized medicine that improves outcomes and reduces unnecessary side effects.
A New Lens for Breast Cancer Research
These discoveries offer a new lens for how we think about breast cancer. Instead of viewing it purely through genetic mutations, we can now appreciate the dynamic and reversible nature of cell identity. By targeting the epigenetic regulators like TET2 and FOXP1, we may be able to shift the course of the disease.
As a researcher and educator, I am excited about the possibilities this opens up, not just for science, but for the patients and families who face this disease every day. Cell fate may be determined by small molecular switches, but by understanding and targeting them, we can make a big difference in people’s lives.