The History of Breast Cancer Treatments and the Misguided War on Estrogen
Introduction: Why Hormones Matter
If you’re going through perimenopause or menopause, you’ve probably heard conflicting messages about estrogen—some that spark curiosity and others that fuel fear. It’s no wonder many women feel uncertain about hormone replacement therapy (HRT), especially if they have a personal or family history of breast cancer. But let’s look at how the “war on estrogen” came to be and why a more nuanced understanding can make all the difference.
Estrogen is not a “cancer trigger.” It’s a hormone that keeps your bones strong, protects your heart, supports brain function, and maintains healthy urinary and vaginal tissues (and so much more!). When medical providers categorically refuse to discuss hormone therapy with women who’ve had breast cancer, they may be overlooking estrogen’s protective benefits—and missing an opportunity for more personalized care.
Early Discoveries: Estrogen Depletion as a First Attempt
In 1896, Dr. George Beatson observed that removing the ovaries (oophorectomy) could temporarily shrink metastatic breast tumors in some premenopausal women. By the 1940s, Dr. Alexander Haddow found that only about 30% of patients responded to estrogen depletion. Although this success rate was modest, it set the bar for future attempts to lower or block estrogen in breast cancer treatment.
The problem? Our bodies are dynamic. When an essential hormone is suddenly removed, we adapt in unpredictable ways. Eventually, most tumors became resistant, and physicians had to look for other strategies.
The Surprising Turn: High-Dose Estrogen Therapy
Interestingly, high-dose estrogen therapy (using diethylstilbestrol, or DES) emerged in the 1940s as another way to treat metastatic breast cancer—also with about a 30% response rate. Since it didn’t require surgery, it was hailed as a breakthrough, though DES later fell out of favor due to other serious health concerns.
The Rise of Tamoxifen and Aromatase Inhibitors
By the 1970s, anti-estrogen drugs like tamoxifen came on the scene. Originally developed as a contraceptive, tamoxifen was later repurposed to block estrogen receptors in breast tissue. It can be effective but carries its own risks, such as increased chances of endometrial cancer and blood clots.
Later, aromatase inhibitors (AIs)—like anastrozole, letrozole, and exemestane—were developed to prevent the conversion of testosterone to estrogen. Essentially, they mimic the effect of surgical ovary removal by drastically reducing estrogen levels. While these medications can be beneficial in certain cases, the notion that “lower estrogen is always better” doesn’t reflect the full complexity of how tumors behave—or the fact that many breast cancers arise in postmenopausal women who already have low hormone levels.
The Three Phases of Antiestrogen Administration
In 2015, Dr. Zsuzsanna Suba outlined three distinct stages that can occur when using anti-estrogen treatments (like tamoxifen or aromatase inhibitors). These phases shed light on how and why resistance develops.
Phase 1: Tumor Regression (Successful Treatment)
Initially, the body compensates for lower estrogen by increasing estrogen receptor (ER) activity. This controlled signal can lead to tumor shrinkage, which is why many patients respond well at first.
Phase 2: Stability (No Progression, But No Further Shrinkage)
Over time, the tumor adapts by producing more estrogen receptors and aromatase, trying to preserve some estrogen signaling. The tumor may stop growing but also stops shrinking. Doctors often interpret this as resistance, but it’s actually the body’s way of restoring balance.
Phase 3: Exhaustion and Rapid Tumor Growth
Eventually, the tumor can’t compensate any longer. The body is depleted of estrogen, and without that signaling, the cancer cells can grow more aggressively and spread. This is often called “acquired resistance,” but it’s the end-stage result of prolonged estrogen deprivation.
Dr. Suba also points out that around half of ER-positive patients don’t respond to anti-estrogen treatments at all—sometimes called “de novo resistance.” This may be linked to hidden genetic mutations that prevent cells from upregulating estrogen receptors or producing extra estrogen when needed.
Anti-Estrogen Therapy and the Metastasis Puzzle
Even in patients who initially respond well to drugs like tamoxifen, prolonged estrogen deprivation can lead to resistance. In some cases, reintroducing high-dose estrogen can actually shrink these “resistant” tumors again—suggesting that a balanced level of estrogen signaling is crucial for long-term control.
Estrogen’s Role in DNA Repair
Recent research by Dr. Lia Yedidia-Aryeh (2022) adds to this complexity. It shows that estrogen supports DNA repair. When estrogen levels drop too low, cells can easily accumulate harmful mutations. This challenges the old idea that “all estrogen is bad” and emphasizes its protective functions in the body.
Rethinking the “War on Estrogen”
Despite their widespread use, anti-estrogen therapies like tamoxifen and aromatase inhibitors only achieve a 30–50% tumor response rate in women with ER-positive breast cancer. In other words, 50–70% of tumors do not respond.
Why, then, have anti-estrogen therapies become the gold standard in breast cancer care?
The answer lies partly in historical precedent and partly in our limited understanding of breast cancer’s complexity when these treatments were first developed. For the subset of patients who respond, these drugs can slow or shrink tumors—at least for a while. However, blocking estrogen throughout the body has serious long-term consequences for bone health, cardiovascular function, cognitive well-being, and more.
Women deserve the opportunity to weigh the benefits and risks of any therapy in the context of their personal and family histories, genetic factors, and overall health goals. Breast cancer doesn’t exist in a vacuum of estrogen alone. Research shows that non-hormonal growth factors, estrogen mimicking chemicals, synthetic estrogens such as ethinyl estradiol, and various signaling pathways —can drive tumor growth even when estrogen levels are minimized. These complexities are rarely discussed in routine care, leaving many women with an incomplete picture of their options.
These facts underscore the need for a more holistic, personalized approach to breast cancer care—one that recognizes the role of estrogen but also accounts for the multitude of other factors that influence tumor growth and overall health.
If you’ve felt anxious or dismissed about the possibility of hormone therapy, remember that the story of estrogen is far more layered than “it causes cancer.” Research increasingly shows that controlled, balanced estrogen signaling may be beneficial—even in many breast cancer cases—when carefully monitored.
Ultimately, you deserve individualized care informed by the latest science. And when it comes to your body, you deserve to make your own medical choices.
References
Suba, Zsuzsanna. “Rosetta Stone for Cancer Cure: Comparison of the Anticancer Capacity of Endogenous Estrogens, Synthetic Estrogens and Antiestrogens.” Oncology reviews vol. 17 10708. 19 Apr. 2023, doi:10.3389/or.2023.10708
Osborne CK, Schiff R. (2011). Mechanisms of Endocrine Resistance in Breast Cancer. Annual Review of Medicine, 62, 233–247.
Suba, Zsuzsanna. “The pitfall of the transient, inconsistent anticancer capacity of antiestrogens and the mechanism of apparent antiestrogen resistance.” Drug design, development and therapy vol. 9 4341-53. 6 Aug. 2015, doi:10.2147/DDDT.S89536
Suba, Zsuzsanna. “Causal Therapy of Breast Cancer Irrelevant of Age, Tumor Stage and ER-Status: Stimulation of Estrogen Signaling Coupled With Breast Conserving Surgery.” Recent patents on anti-cancer drug discovery vol. 11,3 (2016): 254-66. doi:10.2174/1574892811666160415160211
Suba Z (2016) Estrogen Withdrawal by Oophorectomy as Presumed Anticancer Means is a Major Medical Mistake. J Family Med Community Health 3(3): 1081.
Jordan VC. (2003). Tamoxifen: A Most Unlikely Pioneering Medicine. Nature Reviews Drug Discovery, 2(3), 205–213.
Hershman DL, et al. (2010). Side Effects of Aromatase Inhibitors in Breast Cancer. Journal of Clinical Oncology, 28(8), 1263–1269.
Hanahan D, Weinberg RA. (2011). Hallmarks of Cancer: The Next Generation. Cell, 144(5), 646–674.
Arteaga CL, et al. (2012). Treatment of HER2-Positive Breast Cancer: Current Status and Future Perspectives. Nature Reviews Clinical Oncology, 9(1), 16–32.
Braithwaite, R Scott et al. “Meta-analysis of vascular and neoplastic events associated with tamoxifen.” Journal of general internal medicine vol. 18,11 (2003): 937-47. doi:10.1046/j.1525-1497.2003.20724.x
Hartley, Michael C et al. “Differential expression of prognostic factors and effect on survival in young (< or =40) breast cancer patients: a case-control study.” The American surgeon vol. 72,12 (2006): 1189-94; discussion 1194-5.
Suba, Zsuzsanna. “Diverse pathomechanisms leading to the breakdown of cellular estrogen surveillance and breast cancer development: new therapeutic strategies.” Drug design, development and therapy vol. 8 1381-90. 11 Sep. 2014, doi:10.2147/DDDT.S70570
Suba, Zsuzsanna. “DNA stabilization by the upregulation of estrogen signaling in BRCA gene mutation carriers.” Drug design, development and therapy vol. 9 2663-75. 15 May. 2015, doi:10.2147/DDDT.S84437
van Landeghem, A A et al. “Endogenous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue.” Cancer research vol. 45,6 (1985): 2900-6.
Bulun, Serdar E et al. “Aromatase, breast cancer and obesity: a complex interaction.” Trends in endocrinology and metabolism: TEM vol. 23,2 (2012): 83-9. doi:10.1016/j.tem.2011.10.003
Suba, Zsuzsanna. “Circulatory estrogen level protects against breast cancer in obese women.” Recent patents on anti-cancer drug discovery vol. 8,2 (2013): 154-67. doi:10.2174/1574892811308020004
Bollet, Marc A et al. “Tumor aromatase expression as a prognostic factor for local control in young breast cancer patients after breast-conserving treatment.” Breast cancer research : BCR vol. 11,4 (2009): R54. doi:10.1186/bcr2343
Ingle, James N., et al. “Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer.” New England Journal of Medicine 304.1 (1981): 16-21.
Shete, Nivida, Jordan Calabrese, and Debra A. Tonetti. “Revisiting Estrogen for the treatment of endocrine-resistant breast cancer: novel therapeutic approaches.” Cancers 15.14 (2023): 3647.
Rajan, Arathi, et al. “Deregulated estrogen receptor signaling and DNA damage response in breast tumorigenesis.” Biochimica et Biophysica Acta (BBA)-Reviews on Cancer 1875.1 (2021): 188482.
Yoshida, Kiyotsugu, and Yoshio Miki. “Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage.” Cancer science 95.11 (2004): 866-871.
Yedidia-Aryeh, Lia, and Michal Goldberg. “The Interplay between the Cellular Response to DNA Double-Strand Breaks and Estrogen.” Cells 11.19 (2022): 3097.
Zach, L.; Yedidia-Aryeh, L.; Goldberg, M. Estrogen and DNA damage modulate mRNA levels of genes involved in homologous recombination repair in estrogen-deprived cells. J. Transl. Genet. Genom. 2022, 6, 266–280
Liu S, Ruan X, Schultz S, et al. Oestetrol stimulates proliferation and oestrogen receptor expression in breast cancer cell lines: comparison of four oestrogens. Eur J Contracept Reprod Health Care. 2015;20(1):29–35.
Stoica GE, Franke TF, Moroni M, et al. Effect of estradiol on estrogen receptor-alpha gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway. Oncogene. 2003;22(39):7998–8011.
Tolhurst RS, Thomas RS, Kyle FJ, et al. Transient over-expression of estrogen receptor- alpha in breast cancer cells promotes cell survival and estrogen-independent growth. Breast Cancer Res Treat. 2011;128(2):357–368.