Advanced Imaging Reveals Why Some Breast Cancers Resist Treatment

Advanced Imaging Reveals Why Some Breast Cancers Resist Treatment

September, 2025

Breast cancer continues to affect millions of people around the world—and for most, the diagnosis involves a hormone receptor-positive subtype.1

These cancers grow in response to estrogen or progesterone, using hormone receptors on their cells like switches to fuel tumor development.

For years, tamoxifen has been a go-to treatment. It works by blocking those switches, cutting off the cancer’s ability to grow. However, not all patients respond to tamoxifen therapy equally well, with a large proportion of patients showing drug resistance, leaving doctors with fewer options and unanswered questions.2

One study is now helping to explain why. Researchers have identified that the loss of a tumor-suppressing protein called FRMD8 could be part of the reason tamoxifen stops working. Without FRMD8, the tumor’s environment starts to shift in ways that seem to make the drug less effective.3

This discovery was made possible thanks to advanced imaging and analysis tools from TissueGnostics. These technologies allowed scientists to study breast tissue at an extraordinary level of detail—revealing changes that wouldn’t have been visible before, and bringing us one step closer to understanding how this type of resistance develops.

Measuring Key Markers for Tamoxifen Resistance

Cancer cells don’t exist in isolation—they constantly interact with the tissue around them, immune cells, and a wide network of signaling molecules. Together, these form what’s known as the tumor microenvironment. This environment plays a crucial role in how cancers grow, evolve, and respond to treatment.4 This means that, in order to fully understand the factors affecting tumor growth, scientists must consider the entire microenvironment, rather than any single component in isolation.

In this study, the researchers investigated how FRMD8 loss affected the tumor microenvironment. They measured the levels of three important markers:

• ERα (Estrogen Receptor alpha), most commonly expressed hormone receptor in breast tumors
• PR (Progesterone Receptor), encoded by a target gene of ER
• CK8 (Cytokeratin 8), a marker of mammary luminal epithelium

These markers were analyzed in the tissue surrounding the tumor to see how FRMD8 loss might influence the wider environment—not just the tumor itself.

Adapted from Loss function of tumor suppressor FRMD8 confers resistance to tamoxifen therapy via a dual mechanism by Wu et al, 2025.  Figure 3A. Representative multiplex immunofluorescence images of tumor tissues and tissues adjacent to tumor from MMTV-Cre-; Frmd8fl/fl; PyMT and MMTV-Cre+; Frmd8fl/fl; PyMT mice. Scale bar, 50 μm.

Hormone receptor markers are used to help guide treatment decisions in breast cancer care. When their levels drop, it often means there are fewer targets for tamoxifen to act on—raising the risk that the drug may not work as intended. By mapping these markers across the tissue, the researchers were able to visualize that CK8-positive epithelial cells of murine mammary tissues lacking FRMD8 express significantly less hormone receptors compared to control mice. In young FRMD8-deficient mice researchers noted decreased expression of ERα in normal and atypical hyperplasia breast tissues. Overall, the study suggests that lack of FRMD8 causes reduced expression of both ERα and PR in mammary tissues.

Loss of FRMD8 Contributes to Tamoxifen Resistance

FRMD8 plays an important role in maintaining healthy tissue structure and regulating cell signaling. The study found that when this protein is absent, levels of Erα and PR drop significantly in the tissue around mammary tumors, which can at least partially explain tamoxifen resistance mechanism.

While the exact biological mechanisms are still being investigated, early evidence suggests that FRMD8 may influence the production and stability of the hormone receptors tamoxifen needs to target. The study investigated the FRMD8/FOXO3A regulatory axis and showed that FRMD8 silencing dramatically decreased the level of FOXO3A, a transcription factor of Erα. Additionally, the research team suggests that FRMD8 confers stability to Erα protein by inhibiting its degradation.

This link between FRMD8 loss and treatment resistance could give clinicians a valuable tool for predicting which patients might be at greater risk of therapy failure—and allow them to adjust accordingly.

Advanced Imaging and Analysis in Cancer Research

The advanced imaging technology from TissueGnostics used in this study allowed researchers to visualize the tumor microenvironment in depth. The study demonstrates how powerful cutting-edge imaging tools can be in revealing hidden drivers of treatment resistance.

The TSA kit from TissueGnostics was used to amplify the fluorescent signals, making each of the markers clearly visible. Multiplex immunofluorescence (mIF) allowed the research team to detect several different proteins in the same piece of tissue at once. This meant the researchers could confidently detect ERα, PR, and CK8 expression between samples with and without the presence of FRMD8.

Next, the tissues were scanned using the TissueFAXS automated slide scanning platform. TissueFAXS is capable of imaging up to eight fluorescent channels, providing high-resolution, images of whole slides, and provided the researchers with a complete, accurate visual record of where each of the proteins appeared across the full tissue sample.4 The scanned images were then analyzed using StrataQuest image analysis software at the single cell level. This allowed the researchers to measure expression of proteins and is designed to pinpoint the arrangement of ERα, PR, and CK8 and compare the levels of each marker in wild-type or FRMD8-deficient mice models.5

The Future of Breast Cancer Research

This study marks an important step in understanding how loss of FRMD8 contributes to tamoxifen resistance. While further research is needed to validate these findings in larger patient groups and explore how this knowledge could lead to new interventions, the implications are promising.

It is clear that understanding the tumor microenvironment, and how molecules like FRMD8 influence it, will remain a key tool in the ongoing effort to effectively treat breast cancer.

The study highlights both the complexity of the tumor microenvironment and the value of the technology helping to guide our understanding of it. Advanced imaging tools will continue to play a vital role in studies such as this, paving the way to a reduction in breast cancer related deaths worldwide.

At the same time, this work showcases the value of advanced imaging tools in uncovering hidden aspects of disease. By revealing the subtle dynamics of breast tissue at the cellular level, technologies like those from TissueGnostics are helping researchers unlock insights that were previously out of reach.

Contact the team at TissueGnostics today to discover how multiplex immunofluorescence solutions, including the TSA Kit (currently available for Chinese market), TissueFAXS imaging platform, and StrataQuest image analysis software, can provide precise, high-quality data to advance your research and help uncover new insights in cancer biology.

 

Resources

1. Breast cancer [online] World Health Organisation, Available at https://www.who.int/news-room/fact-sheets/detail/breast-cancer [accessed 11th August 2025]
2. Maselli A et al. (2019) Autoantibodies Specific to ERα are Involved in Tamoxifen Resistance in Hormone Receptor Positive Breast Cancer, Cells. 19;8(7):750
3. Wu W et al. (2025) Loss function of tumor suppressor FRMD8 confers resistance to tamoxifen therapy via a dual mechanism, eLife. 13
4. Anderson NM, Simon MC. (2020) The tumor microenvironment. Curr Biol. Aug 17;30(16):R921-R925.
5. StrataQuest [Online] TissueGnostics, Available at https://tissuegnostics.com/products/contextual-image-analysis/strataquest [accessed 11th August 2025]