Exploring the groundbreaking research that's transforming our understanding of hormone-driven cancers
When a young oncologist named Myles Brown watched a patient's breast cancer tumors initially shrink with tamoxifen treatment only to return months later, he became obsessed with a fundamental question: How do cancer cells outsmart our best therapies? This clinical mystery launched a decades-long scientific quest that would transform our understanding of how hormones influence cancer and ultimately reshape treatment approaches for millions of patients worldwide. Brown's journey from bedside to laboratory represents one of the most compelling stories in modern cancer research—a story of molecular detective work that has revealed cancer's remarkable adaptability while pointing toward more effective strategies to overcome treatment resistance.
Dr. Myles Brown stands today as one of the world's leading authorities on hormone-dependent cancers, serving as the Emil Frei III Professor of Medicine at Harvard Medical School and Director of the Center for Functional Cancer Epigenetics at Dana-Farber Cancer Institute 3 5 . His election to the National Academy of Sciences, National Academy of Medicine, and American Academy of Arts and Sciences reflects the extraordinary impact of his research on our understanding of breast and prostate cancers 5 .
Through his pioneering work, Brown has not only illuminated the intricate dance between hormones, their receptors, and our DNA but has also opened new pathways for overcoming one of oncology's most persistent challenges: treatment resistance.
At the heart of Brown's research are nuclear receptors—specialized proteins that act as molecular switches controlling which genes are turned on or off in response to hormonal signals. These receptors, including the estrogen receptor (ER) in breast cancer and the androgen receptor (AR) in prostate cancer, play pivotal roles in determining cell behavior. When activated by hormones, these receptors bind to specific regions of DNA and initiate programs of gene expression that can either maintain healthy cell function or drive cancerous growth when dysregulated.
Brown's early breakthrough came when he recognized that these receptors don't work alone. His laboratory discovered a critical family of coactivator proteins (termed p160 coactivators) that serve as essential partners in gene activation 3 8 . These coactivators function as molecular bridges between the hormone-receptor complex and the cellular machinery that transcribes DNA into RNA. Without them, hormonal signals fail to properly execute their instructions—like having a key without the proper mechanism to unlock the door.
Perhaps even more significant was Brown's discovery that these coactivators assemble in a precise, ordered sequence rather than randomly attaching to receptors 6 . This finding revealed that hormone signaling follows an elaborate choreography—a carefully timed molecular dance where each participant must enter at the right moment for proper gene activation to occur. This sophisticated understanding explained how the same hormone receptor could regulate different genes in various tissues, providing insights into both normal physiology and cancerous states.
| Discovery | Year | Significance | Impact |
|---|---|---|---|
| p160 coactivators | 1990s | First identification of proteins that enhance steroid receptor function | Explained tissue-specific hormone responses |
| Ordered coactivator assembly | 2000 | Revealed precise sequence of molecular interactions | Provided new therapeutic targeting opportunities |
| Enhancer-based receptor binding | 2008 | Demonstrated receptors primarily bind distant from genes | Transformed understanding of gene regulation |
| Cistrome concept | 2010 | Developed framework for genome-wide binding analysis | Created new paradigm in genomic research |
In collaboration with computational biologist Dr. X. Shirley Liu, Brown pioneered the concept of the "cistrome"—the complete set of DNA binding sites for a particular transcription factor across the entire genome 2 8 . This breakthrough emerged from their work using ChIP-seq (Chromatin Immunoprecipitation followed by sequencing), a powerful technique that allows researchers to identify where proteins bind to DNA throughout the genome.
Rather than finding estrogen receptors bound primarily near the start of genes (as previously assumed), Brown and Liu discovered these receptors mostly interact with distant enhancer regions—sometimes hundreds of thousands of bases away from the genes they regulate 6 . These enhancers act like genetic "control centers" that can remotely activate specific genes through DNA looping. This fundamental reorganization of our understanding of gene regulation explained how the same receptor could have diverse effects in different tissues and disease states.
Brown's work revealed that hormone receptors bind primarily to distant enhancer regions, not gene promoters
One of Brown's most significant recent contributions came through applying CRISPR-Cas9 gene editing technology to understand treatment resistance in estrogen receptor-positive (ER+) breast cancer 6 . The research team designed a comprehensive genetic screen to identify which genes affect the survival of ER+ breast cancer cells when treated with anti-estrogen therapies.
The team created a collection of guide RNAs targeting every known protein-coding gene in the human genome—approximately 20,000 genes in total.
These guide RNAs were delivered into ER+ breast cancer cells using lentiviral vectors, ensuring each cell received only one guide RNA.
The researchers treated the cells with tamoxifen or other estrogen-blocking agents, creating strong selective pressure.
After several weeks, they sequenced the surviving cells to determine which guide RNAs were overrepresented.
The results were both validating and surprising. As Brown noted: "What was gratifying was that the top genes we found to be essential for the estrogen-stimulated growth of ER-positive breast cancers were ones we had been identifying over the last couple of decades—transcription factors like FOXA1 and GATA3" 6 . This confirmation reinforced decades of prior research while demonstrating the power of unbiased genetic screens.
Most importantly, the screen revealed a previously unknown negative feedback loop involving a gene called c-terminal SRC kinase (CSK). Here's how it works: estrogen stimulates the ER to turn on growth genes but simultaneously activates CSK, which inhibits SRC family members and limits how strongly estrogen stimulates cell growth. When therapies block estrogen signaling, they inadvertently remove this braking mechanism, allowing SRC signaling to run wild and reactivate growth pathways through alternative routes.
| Gene | Function | Role in Treatment Resistance |
|---|---|---|
| FOXA1 | Transcription factor | Maintains breast cell identity and ER signaling |
| GATA3 | Transcription factor | Regulates luminal cell differentiation |
| CSK | Kinase | Negative regulator of SRC family kinases |
| PAK2 | Kinase | Downstream effector of SRC signaling |
Further investigation revealed that when CSK is inhibited, another gene downstream called PAK2 becomes essential for cancer survival 6 . This discovery pointed toward a promising combination therapy approach: simultaneously targeting the estrogen receptor and PAK2 might more completely block cancer growth pathways and prevent resistance from emerging.
The research team validated this approach in laboratory models, demonstrating that dual inhibition of ER and PAK2 signaling more effectively suppressed cancer growth than targeting either pathway alone. This critical finding provides a roadmap for developing next-generation combination therapies that could significantly improve outcomes for patients with hormone receptor-positive breast cancers.
Brown's groundbreaking discoveries were made possible by advanced research tools and reagents that have transformed cancer biology. These technologies allowed his team to interrogate molecular processes with unprecedented precision and scale.
Identifies protein-DNA binding sites genome-wide. Essential for mapping estrogen receptor binding sites throughout the genome.
Precise gene editing using guide RNA and Cas9 nuclease. Enabled genome-wide screens for treatment resistance genes.
Gene silencing using RNA interference. Critical for validating the function of individual genes identified in screens.
Specifically detect and isolate coactivator proteins. Essential for studying protein interactions and mapping transcription factors.
The sophisticated application of these tools has been essential to Brown's success. As he advises young scientists: "Be self-critical, but trust your own data and don't be dissuaded by reviewers of papers and grants" . This balanced approach—combining cutting-edge technology with scientific conviction—has characterized Brown's influential career.
Brown's research has fundamentally reshaped how we approach hormone-driven cancers. His discoveries about coactivators and receptor function have informed the development of more selective hormone therapies with improved efficacy and reduced side effects. The conceptual framework provided by his work on cistromes and enhancer function has helped explain why some patients respond to certain therapies while others develop resistance.
Most recently, Brown has extended his research to explore how obesity affects anti-tumor immunity in triple-negative breast cancer (TNBC) 4 . His team has found that obesity promotes cancer growth in laboratory models and dramatically alters the immune environment within fat tissues. Specifically, obesity increases certain immune cells that interact with tumor cells in ways that prevent other immune cells from attacking the cancer.
In intriguing findings, Brown's team discovered that tumor growth was inhibited in models where weight loss was induced—either through diet or treatment with GLP-1 receptor agonists (the class of drugs that includes Ozempic and Wegovy) 4 . This unexpected connection between metabolism, immunity, and cancer growth opens exciting new avenues for combination therapies that might enhance the effectiveness of immunotherapies in breast cancer patients.
Brown is now working to understand the mechanism by which weight reduction restores the immune system's ability to control tumor growth. "Elucidating this mechanism," he explains, "will help identify novel targets for the treatment of patients with breast cancer who have obesity" 4 . This research direction exemplifies Brown's ability to follow the science where it leads, even when it moves beyond traditionally defined areas of hormone signaling.
Myles Brown's career exemplifies the power of translational research—the bidirectional flow of knowledge between laboratory and clinic. His journey began with a clinical observation (tamoxifen resistance) that sparked fundamental questions about basic biology, and the answers to those questions are now circling back to inform new therapeutic approaches for cancer patients.
In recognition of his contributions, Brown received the Gerald D. Aurbach Award for Outstanding Translational Research from the Endocrine Society in 2023 . This honor reflects how his work has "fundamentally reformulated the mechanistic understanding of hormone dependence of breast and prostate cancers," enabling the development of new therapies for these diseases.
For aspiring scientists, Brown offers simple but powerful advice: "Pick an important problem that you feel passionate about and stick with it" . His career demonstrates the cumulative power of sustained focus on fundamental biological questions—how each discovery builds upon previous findings to create a transformative body of work.
As Brown's research continues to evolve, exploring the intersections between hormone signaling, cancer metabolism, and immunotherapy, his legacy serves as a powerful reminder that today's basic scientific investigations often become tomorrow's medical breakthroughs. Through his dedicated pursuit of cancer's molecular secrets, Myles Brown has not only expanded the boundaries of knowledge but has also provided hope for countless patients affected by hormone-driven cancers.