Each year, more than 310,000 women and 2,700 men in the U.S. are diagnosed with breast cancer. In Wisconsin alone, nearly 6,000 new cases are expected in 2025. Behind these numbers are people facing life-changing diagnoses—and researchers racing to understand the complexities of breast cancer and turn that knowledge into better care.
At the MCW Cancer Center, Todd Miller, PhD, Wisconsin Breast Cancer Showhouse (WBCS) Endowed Professor of Breast Cancer Research and Professor of Pharmacology & Toxicology and Pathology, leads a lab dedicated to unraveling one of cancer’s most complex puzzles: why breast cancer adapts, resists treatment, and returns long after therapy ends.
Dr. Miller began his career in neurology, studying Huntington’s disease, but grew frustrated by how long it took for discoveries to make a difference for patients. Seeking a field where research could more directly influence care, he turned to oncology. After earning his PhD in 2004, he joined Vanderbilt University to study breast cancer and, in 2012 at the Dartmouth Cancer Center, established his own lab focused on estrogen receptor–positive (ER+) disease. That decision shaped his career and his approach to science, one that finds clarity in complexity and keeps patients at the center of discovery.
“Every patient is unique, and therefore every tumor is unique. A one-size-fits-most approach oversimplifies a complex problem. By deepening our understanding of how cancer cells function in different contexts, we can refine treatments that are truly personalized and, ultimately, more effective,” said Dr. Miller.
Seeing Possibility Where Others See Paradox
Breast cancer is not a single disease but a group of related subtypes, each with distinct biological traits that determine how it grows, spreads, and responds to treatment. ER+ breast cancer, the most common and biologically intricate form of the cancer, accounts for about 70% of all cases. Although these tumors grow slowly, they are remarkably persistent. Even after surgery and years of anti-estrogen therapy, about one in three patients experiences recurrence, sometimes decades after initial treatment.
“ER+ disease plays the long game. Our biggest challenge is finding ways to prevent or delay recurrence and make advanced disease a chronic, manageable condition,” said Dr. Miller.
One of the Miller Lab’s most innovative projects takes an unexpected approach: reintroducing estrogen itself as a therapy. “It sounds counterintuitive,” he explained, “but in some patients, estrogen can actually shrink tumors that no longer respond to other treatments.”
In a recent clinical study co-designed by Dr. Miller, two of 19 patients with metastatic ER+ breast cancer experienced tumor regression, while cancer growth remained stable in six others for more than 24 weeks. These findings raised a critical question: why does estrogen kill some resistant cancer cells but not others?
To find out, PhD candidate Alyssa Roberts, postdoctoral fellow Anneka Johnson, and lab manager Kim Birmingham are investigating what happens inside cancer cells during treatment. Their work suggests that a sudden flood of estrogen causes DNA damage in tumors that had adapted to grow without it. The team is now testing combinations that could amplify this effect using drugs known as PARP inhibitors, which block an enzyme cancer cells rely on to repair damaged DNA.
“Not all PARP inhibitors work the same. Some PARP inhibitors just prevent DNA repair while others can also stick to the DNA. This sticking seems to push cancer cells past the point of survival specifically when paired with estrogen therapy,” said Roberts.
From Discovery to Delivery
The Miller Lab is also exploring how changes in metabolism help cancer survive therapy. MD/PhD candidate Malone Friedman and postdoctoral fellow Yu-Zhou (Joe) Huang found that therapy-resistant ER+ cancer cells accumulate a type of fat molecule called polyunsaturated fatty acids (PUFAs). While PUFAs are essential for normal cell health, in excess they can oxidize and damage the cell membrane. The team is testing whether pushing cancer cells toward this metabolic stress can trigger their death. In parallel, they’re using large-scale genetic screens to identify additional metabolic “weak spots” that could be targeted by new drugs.
The lab’s next step brings this concept into the clinic. In collaboration with breast oncologist Lubna Chaudhary, MD, and the Cancer Center Breast Disease-Oriented Team, Dr. Miller is launching a clinical trial to test whether omega-3 PUFA supplements can alter the lipid composition of ER+ tumors in ways that make them more sensitive to therapy. “We are what we eat, and the same applies to cancer cells,” Dr. Miller said. “If we can change their metabolism, we may change their fate.”
Another research area focuses on tumor dormancy, the stage when microscopic clusters of cancer cells remain inactive for years before reawakening. Dr. Miller’s lab is studying how these cells survive in a dormant state and what triggers their return, using advanced imaging and molecular profiling tools to identify the moment they become vulnerable. This work may help researchers target cancer cells at their quietest—and most treatable—stage.
Together, these projects feed into a precision medicine framework that connects lab findings directly to patient care. By identifying key genetic markers and linking them to treatment responses, the team aims to predict who will benefit most from specific therapies. “The goal is to move from trial-and-error treatment toward a future where every therapy is informed by biology, timing, and patient context,” said Dr. Miller.
Training Scientists to Think Like Clinicians
Dr. Miller’s translational mindset extends beyond his own lab. At the Cancer Center, he co-leads the Discovery and Developmental Therapeutics Program, which unites scientists and clinicians to discover, develop, and test new cancer therapies. Together, these efforts ensure that promising insights move efficiently from the lab bench to the patient’s bedside.
Inside the Miller Lab, that same philosophy takes on a personal dimension. Projects are designed with the end in mind and framed around two questions: will these findings deepen our understanding of cancer biology or management, and how will they help people affected by cancer? The lab’s culture thrives on collaboration, curiosity, and mentorship. Each team member is encouraged to think about the patient connection behind every experiment and to uphold the highest standards of rigor, integrity, and reproducibility.
For Dr. Miller, mentorship is as important as discovery. He tailors his guidance to each trainee, fostering an environment where questions are welcomed, ideas are shared, and science is both personal and purposeful.
“Todd’s mentoring style is different for every student. He strikes the perfect balance between giving students an important starting spot and helping them explore their own ideas,” said Johnson.
Philanthropy plays a vital role in sustaining this work, and support from WBCS helps make it possible. The all-volunteer nonprofit, founded in 1998 to advance early-stage breast and prostate cancer research at the Cancer Center, has had a $145 million research impact through its ongoing commitment to discovery. Through Dr. Miller’s endowed professorship, WBCS provides flexible resources that enable his team to pursue high-reward ideas, refine biomarker strategies, and launch pilot studies that position the most promising findings for clinical testing.
Additional efforts like Audaxity, where Dr. Miller rides with Team Pink Pedals Prevail, are helping ensure that more of this research reaches patients faster. For patients in Wisconsin, that kind of early investment shortens the distance from insight to intervention.
“The science is strong,” said Dr. Miller. “But science alone isn’t enough. What drives me is seeing discoveries move beyond the lab and turning what we learn about cancer’s biology into therapies that genuinely improve patients’ lives. That’s success, and that’s what keeps me focused.”
Get to know the Miller Lab.