Could There Be Another Explanation? Rethinking Estrogen, Endocrine Therapy, and Breast Cancer
Published: September 18, 2026
I have been fascinated by the work of Dr. Zsuzsanna Suba for several years. Her interpretation of breast cancer is not mainstream. I kept reading her papers because once I began to understand just how important estradiol is throughout the human body, I could no longer reconcile that physiology with the very simple story we are often told about estrogen and breast cancer.
Estradiol matters in the brain, bone, blood vessels, muscle, metabolism, skin, vagina, vulva, urinary tract, and immune system. It also matters inside our cells. Estrogen signaling helps cells turn certain genes on and off, respond to DNA damage, and coordinate some of the repair systems that help keep DNA working properly. (Caldon, C., 2014; Pescatori, S., et al., 2021).
Yet when breast cancer enters the conversation, this extraordinarily complex regulatory molecule often seems to be reduced to one job: growth.
Estrogen makes cancer grow. Therefore, remove estrogen.
The more I learned about physiology, and the more women I heard from who were struggling profoundly on endocrine therapy, the harder it became for me not to ask: Are we sure that is the whole story?
Some women tolerate endocrine therapy reasonably well. Others describe losing themselves. They talk about painful joints, loss of sexual function, vaginal and vulvar changes, sleep disruption, bone loss, fatigue, cognitive symptoms, mood changes, and a quality of life that feels completely different from the life they had before treatment. Endocrine therapy is well documented to produce significant adverse effects in at least a subset of women, and those effects can contribute to treatment discontinuation (Condorelli, R. & Vaz-Luis, I., 2018).
I have heard women say that living this way feels unbearable. When a treatment interferes with a signaling system that operates throughout the body, perhaps we should not be surprised that the consequences can be felt throughout the body.
That does not prove the treatment is wrong. But it should make us curious.
And that curiosity led me back to a basic question: What if there is another explanation?
Before we go any further, I want to acknowledge that we do have randomized clinical trials show that endocrine therapy reduces breast-cancer recurrence in some women with hormone-receptor-positive disease. That is an outcome. But an outcome does not necessarily tell us the complete mechanism responsible for it. Those are different questions.
We observe that recurrence is lower in one treatment group. Then we develop a biological explanation for why.
The conventional explanation is straightforward. The cancer is estrogen-receptor positive. Estrogen activates the receptor. The receptor stimulates cancer growth. Therefore, block estrogen and decrease tumor growth.
That explanation sounds logical. But biology occasionally gives us results that do not fit such a simple line. And one of the most interesting examples involves estrogen itself.
When Removing Estrogen and Giving Estrogen Can Both Work
This is the paradox that originally stopped me.
Aromatase inhibitors work by profoundly reducing estrogen production. Yet researchers have also treated women with advanced, hormone-receptor-positive breast cancer using estradiol itself.
In a randomized phase 2 trial, women whose cancers had already become resistant to aromatase inhibitors were given either 6 mg or 30 mg of oral estradiol daily. Some experienced tumor responses or prolonged stable disease. The researchers proposed that prolonged estrogen deprivation may actually make certain tumor cells vulnerable to estradiol again (Ellis, M., et al., 2009).
This was metastatic, endocrine-resistant breast cancer. It was not a trial showing that estradiol should replace adjuvant endocrine therapy after early breast cancer. But mechanistically, it raises an enormous question.
If estrogen were simply fuel for every ER-positive cancer cell, then giving substantial doses of estradiol should predictably accelerate the cancer. Yet under certain biological conditions, the opposite happens. The cancer can regress.
That means there is more going on than estrogen equals growth.
This Is Where Dr. Suba Offers a Very Different Explanation
Dr. Suba starts from a very different idea. She does not see estrogen as simply a signal that tells a breast cancer cell to grow. She sees estrogen as part of the system that helps a cell read its DNA, repair damage, and keep its instructions organized.
Think of DNA as the cell’s instruction manual. The cell has to constantly read that manual, use the right instructions, repair damage when it happens, and make sure mistakes do not pile up.
Estrogen helps with some of that work by attaching to the estrogen receptor, or ER.
You can think of the estrogen receptor as a switch inside the cell. When estrogen attaches to it, the switch turns on. That allows the cell to turn certain genes on or off and helps coordinate other proteins involved in DNA repair and cell control.
Some of those repair proteins have names you may recognize, such as BRCA1, BRCA2, ATM, ATR, and p53. These proteins help the cell detect damage, repair mistakes, or stop a badly damaged cell from continuing to grow (Caldon, C., 2014; Pescatori, S., et al., 2021).
Researchers agree that estrogen signaling interacts with these systems. What they do not fully agree on is what that means.
Some researchers focus on the fact that estrogen can help cells grow and divide. Dr. Suba focuses much more on the idea that healthy estrogen signaling also helps keep the cell’s DNA stable and properly regulated.
Essentially, she is challenging the narrative: What if estrogen is not just pressing the gas pedal? What if it is also helping the car stay on the road? That changes how she looks at endocrine therapy.
The usual explanation for how endocrine therapy works is this:
Estrogen helps an ER-positive cancer grow. Endocrine therapy blocks estrogen or lowers estrogen levels, so the cancer loses an important growth signal and the tumor shrinks or stays quiet.
Dr. Suba asks whether something else could also be happening.
Her idea is that when estrogen signaling is blocked, the cell may sense that an important regulatory system is no longer working normally and begin trying to restore it.
It might look like this:
Estrogen signaling is blocked
→ the cell senses that an important signal is missing
→ the cell tries to compensate
→ it may make more estrogen receptors
→ it may turn on other growth and repair pathways
→ it may find other ways to activate the estrogen receptor
→ it may increase local estrogen signaling inside the tissue
→ if those efforts restore enough normal signaling, the damaged cell may stop growing or even die
This is where Dr. Suba’s interpretation is very different from the usual one.
Oncology may look at a shrinking tumor and say: “The treatment worked because we blocked estrogen.”
Dr. Suba asks: “What if the cell improved because it successfully fought back against the estrogen blockade and restored enough normal signaling to regain control?”
Same result. Different explanation.
In her view, what we call a successful response to estrogen deprivation may, at least in some cells, actually be the cell’s attempt to repair the disruption we created (Suba, Z., 2020). The same biological event can be interpreted in two very different ways.
Then What Does “Endocrine Resistance” Mean?
The conventional explanation is that endocrine therapy works by taking away an important growth signal. But not every ER-positive cancer responds the same way. Some cancers appear resistant to endocrine therapy from the beginning, and others initially respond but later begin growing again despite treatment. Reviews commonly estimate that roughly 15% to 30% of ER-positive cancers show resistance from the start, while acquired resistance develops in a substantial minority over time, particularly in advanced disease.
Researchers see changes such as more estrogen receptors, changes that allow the estrogen receptor to stay active with very little estrogen, and increased use of other growth pathways such as HER2, IGF, PI3K, AKT, and MAPK. These changes are usually described as ways the cancer learns to escape endocrine therapy.
Dr. Suba looks at many of those same changes and asks a different question: What if at least some of this is the cell trying to restore a signaling system that we deliberately took away?
She calls these changes compensatory.
In other words, oncology may say, “Look how clever the cancer became. It found another way around the estrogen blockade.”
Dr. Suba asks, “Why is the cell fighting so hard to restore this signaling?”
The Exhaustion Hypothesis
Dr. Suba then takes this one step further.
Imagine holding an essential physiological system down continuously. At first, the body compensates. We see this everywhere in physiology. Take away thyroid hormone, and TSH rises. Decrease blood pressure and regulatory systems activate. Decrease oxygen and the body increases compensatory signals. Human physiology continuously attempts to restore homeostasis (balance).
Why would estrogen signaling be the one exception?
Dr. Suba proposes that when estrogen signaling is blocked, the cell does not simply give up. At first, it may work harder to restore the missing signal. She describes this as a kind of compensation.
In simple terms:
Estrogen is blocked
→ the cell senses that an important control system is missing
→ it tries to make up for that loss
→ it may make more estrogen receptors or turn on other growth and survival pathways
→ for a while, those backup systems may help the cell keep functioning
→ estrogen remains blocked
→ eventually the backup systems may no longer be enough
→ DNA mistakes may build up and normal cell control may become less stable
→ the cancer may begin to grow or progress
Dr. Suba calls this later stage the exhaustion phase.
The idea is that the cell may compensate for estrogen deprivation for a while, but if that deprivation continues long enough, the cell may eventually lose its ability to keep its DNA and growth signals under control. (Suba, Z., 2020)
Mainstream oncology interprets the later tumor progression as the cancer escaping endocrine therapy. Dr. Suba interprets it as the cell finally losing its ability to compensate for endocrine disruption. Same observation. Very different explanation.
What If “Resistance” Is Partly Compensation?
I find this question especially important because the body is full of backup systems. When we block one pathway, cells usually do not just sit there and accept it. They adjust. They try another route. They try to restore balance.
Cancer cells are still human cells. Their signaling may be damaged and disorganized, but they are using the same basic cellular machinery. So maybe at least some of what we call endocrine resistance is the cell trying to get back to a more stable state.
That does not mean the cancer cell is healthy. It does not mean every response the cell makes is helpful. But it changes the question.
Instead of only asking: How do we block the next pathway?
Maybe we should also ask: Why did that pathway turn on in the first place?
And Now the High-Dose Estrogen Paradox Makes More Sense
This is why the estradiol studies are so interesting to me. After cancer cells have been deprived of estrogen for a long time, researchers have found that giving estradiol back can sometimes cause those cells to die instead of grow.
Scientists call this estrogen-induced apoptosis. Apoptosis simply means programmed cell death—the cell gets a signal to shut itself down.
This is a real and recognized finding in breast-cancer research. What researchers still debate is why it happens and what it tells us about estrogen’s normal role in the cell.
In the Ellis trial, women with ER-positive metastatic breast cancer whose cancers had already stopped responding to aromatase inhibitors were given estradiol. Some women had a meaningful response to the estrogen itself (Ellis, M., et al., 2009).
That raises an obvious question: If the relationship were really as simple as more estrogen equals more cancer growth, why would giving estrogen ever make an estrogen-sensitive cancer shrink or stop growing?
Clearly, the biology is more complicated than that.
Estrogen Has a Relationship With the Genome
Estradiol works by attaching to estrogen receptors inside the cell. Once activated, those receptors help turn certain genes on and off.
Think of DNA as the cell’s instruction book. To read a section of that book, the DNA has to open up so the cell can access the instructions it needs.
Proteins called topoisomerases help with this process. One of them, called TOP2, can make tiny temporary breaks in the DNA so it can unwind and be read. Afterward, the cell’s repair machinery is supposed to put everything back together again (Pescatori, S., et al., 2021).
Estrogen signaling also works closely with many of the proteins involved in detecting and repairing DNA damage.
So estrogen is not simply standing outside a cancer cell yelling, “Grow.” It is part of a much larger system that helps cells read genes, respond to damage, and maintain normal cell function.
This is also where the science gets more complicated. Some researchers focus on the possibility that estrogen-related activity can contribute to DNA damage under certain conditions. Others point out that estrogen signaling also helps coordinate normal DNA-repair and protective responses.
Pescatori and colleagues described estradiol as having a dual role. Depending on the situation, it may be involved in both creating DNA stress and helping the cell protect and repair its DNA (Pescatori, S., et al., 2021).
That is a very different story from simply saying: Estrogen makes cancer grow.
Suba’s BRCA Work Pushed Me Even Further
This is one of the reasons I became so interested in Dr. Suba’s work. BRCA1 and BRCA2 are genes that help repair damaged DNA. You can think of them as part of the cell’s repair crew.
Dr. Suba has proposed that when these repair systems are not working normally, the cell may increase estrogen signaling as a way to compensate and try to keep its DNA more stable (Suba, Z., 2015).
And the question she asks is important: If estrogen signaling goes up when a cell is under stress, does that automatically mean estrogen caused the problem? Or could some of that increase be the cell trying to respond to the problem and protect itself?
That is a very different way of looking at the same finding.
Cause or Compensation?
We make this mistake in medicine surprisingly often.
A marker rises during disease. We observe that it is associated with disease. Then we assume that lowering the marker will correct the disease.
Sometimes it does. But oftenimes the marker was part of the body’s attempt to compensate. Those are completely different situations.
Dr. Suba believes estrogen signaling may sometimes be blamed as the cause when it could actually be part of the body’s attempt to restore balance.
Because We Cannot Watch This Happen Inside a Woman
This is where breast-cancer recurrence becomes especially hard to understand.
A woman has surgery. The visible tumor is removed. If a few cancer cells had already escaped before surgery, they may be too small to detect. Some may die. Some may remain quiet for years. Scientists call that dormancy, which simply means the cells are still there but are not actively growing into a tumor.
The problem is that we usually cannot watch those cells over the next 10 or 20 years. We cannot see exactly when one becomes dormant. We cannot watch whether its estrogen receptors change.
We cannot see every message coming from the immune system, bone marrow, blood vessels, or the nearby support cells (called stromal cells) that help make up the tissue around it.
And if the cancer comes back 12 years later, we cannot rewind the woman's biology and watch the exact moment that one of those cells started growing again.
So researchers have to piece the story together. They study cells in the lab. They study animals. They look at patterns of recurrence in women. Then they build models to explain what may have happened. That is how science moves forward.
But it is important to remember the difference between what we actually observed and the explanation we built around it.There May Be More Than One Explanation for the Same Result
Here is the conventional interpretation: Endocrine therapy lowers recurrence because estrogen was driving residual cancer cells.
Here is Dr. Suba’s alternative hypothesis: Endocrine therapy creates estrogen-signaling disruption. Some cells mount a compensatory response strong enough to restore ER signaling and genomic regulation, which may contribute to tumor regression. Cells that eventually cannot compensate develop greater instability and progression.
There are other possibilities too. The truth may contain pieces of several models. But we cannot choose among them simply because one has been repeated more often.
And Now Add Everything We Are Learning About Dormancy
This becomes even more complicated when we look beyond the original tumor.
A breast cancer may be called ER-positive because the original tumor had estrogen receptors. But that does not mean every cancer cell that escaped from that tumor has the same receptors or behaves the same way.
Dormant cancer cells also seem to be affected by many things around them. The immune system matters. Inflammation matters. Bone breakdown and rebuilding matter. Nearby support cells matter. Blood vessels matter. Blood sugar and insulin matter. Aging matters. And the local environment around the cell matters.
Cancer cells also have more than one way to receive growth and survival signals. If one pathway is blocked, another pathway may become more important. That is why breast cancer cannot be understood as a disease controlled by one single switch.
It is not just estrogen on or estrogen off.
So Why Have We Reduced the Conversation to One Molecule?
Estradiol matters all over a woman’s body. It helps support the brain, bones, muscles, blood vessels, metabolism, sexual health, vaginal and urinary tissues, connective tissue, and more.
Aromatase inhibitors, meanwhile, are well known to increase bone loss and fracture risk, along with other side effects that can affect daily life (Amir, E., et al., 2011).
So when a woman says, “My whole body feels different without estrogen,” maybe the answer should not simply be: “That is the price you have to pay because estrogen feeds your cancer.”
Maybe we need to ask more questions:
What are we actually gaining by removing estrogen?
How much does it lower risk for this particular woman?
How long does she need to take it?
What is it costing her in the rest of her body?
And how sure are we that the explanation we are using for why it works is the full story?
I Am Not Asking You to Agree With Dr. Suba
I’m not asking you to agree with me. I’m asking you to consider that there may be more than one biologically plausible way to explain what we are seeing.
Dr. Suba’s interpretation is not the mainstream view of breast-cancer biology. But many parts of the physiology she builds on are very real.
Estradiol is not a simple growth signal. It is a major regulatory hormone that works throughout the body and inside the cell. It helps control gene activity, interacts with DNA-repair pathways, affects metabolism, supports bone and blood vessels, and plays an important role in the brain, muscles, immune system, and reproductive and urinary tissues.
We also know that cells compensate when important signals are lost. We know that cancer cells can change pathways. We know that prolonged estrogen deprivation can change cell behavior. We know that high-dose estradiol can sometimes trigger death in endocrine-resistant breast-cancer cells. And we know that dormant cancer cells are influenced by far more than estrogen alone.
None of that proves every part of Dr. Suba’s model.
But it does make me think her central question deserves much more attention: What if estrogen signaling is not simply something the cancer is using to grow? What if some of that signaling is also part of the cell’s attempt to maintain order, repair damage, and restore balance?
That possibility changes the conversation. And once you understand how deeply estradiol is woven into normal human physiology, it becomes very difficult to reduce it to one sentence: Estrogen makes cancer grow. That explanation is simply too small for the biology.
Maybe We Need to Return to Physiology
Perhaps the question should not always be: What else can we block?
Maybe we should also ask:
What is the body trying to restore?
What happened to the cell’s DNA?
What happened to the systems that normally help control and repair the cell?
What happened to the immune system around it?
What happened to insulin and other growth signals?
What changed in the bone marrow where dormant cells may be hiding?
Why is the cell turning on backup pathways?
And what happens to the rest of a woman’s body when we suppress one of its major regulatory hormones for five or ten years?
Those are harder questions. But women deserve harder questions. Especially when the treatment we are recommending can change how they feel in nearly every part of their body.
We should be able to hold two ideas at the same time: Endocrine therapy has lowered recurrence for some women in randomized trials. And: We may not fully understand why every tumor responds, why some become resistant, or why some cancers return many years later.
Those ideas do not cancel each other out. They should make us more curious. Because sometimes the same result can have more than one explanation. And when the physiology is this complex, I think women deserve more than a simple story. They deserve the full conversation.
References
Amir, E., Seruga, B., Niraula, S., Carlsson, L., & Ocaña, A. (2011). Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. Journal of the National Cancer Institute, 103(17), 1299–1309. https://doi.org/10.1093/jnci/djr242
Caldon, C. E. (2014). Estrogen signaling and the DNA damage response in hormone-dependent breast cancers. Frontiers in Oncology, 4, 106. https://doi.org/10.3389/fonc.2014.00106
Condorelli, R., & Vaz-Luis, I. (2018). Managing side effects in adjuvant endocrine therapy for breast cancer. Expert Review of Anticancer Therapy, 18(11), 1101–1112. https://doi.org/10.1080/14737140.2018.1520096
Ellis, M. J., Gao, F., Dehdashti, F., et al. (2009). Lower-dose versus high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: A randomized phase 2 study. JAMA, 302(7), 774–780. https://doi.org/10.1001/jama.2009.1204
Pescatori, S., Berardinelli, F., Albanesi, J., et al. (2021). A tale of ice and fire: The dual role for 17β-estradiol in balancing DNA damage and genome integrity. Cancers, 13(7), 1583. https://doi.org/10.3390/cancers13071583
Suba, Z. (2015). DNA stabilization by the upregulation of estrogen signaling in BRCA gene mutation carriers. Drug Design, Development and Therapy, 9, 2663–2675. https://doi.org/10.2147/DDDT.S84437
Suba, Z. (2020). Compensatory estrogen signal is capable of DNA repair in antiestrogen-responsive cancer cells via activating mutations. Journal of Oncology, 2020, 5418365. https://doi.org/10.1155/2020/5418365
Disclaimer: This article is for educational and informational purposes only and is not intended to replace personalized medical advice or individualized care. It is meant to help you understand your physiology, explore evidence-based options, and make informed choices about your health and wellness. Healthcare should be a partnership, not a permission slip, and proactive care is just as essential as treatment. Use this information to engage in open, collaborative discussions with your provider or to make empowered decisions that align with your own values, goals, and comfort level. You are the ultimate authority on your body.