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Abstract
Breast cancer is unique with so many complexities like precancerous growth enhancing factors including mechanism in-vivo for metastasis and acquisition of resistance to chemotherapy and radiation. Estrogen adjuvant therapy was considered a success in the beginning since synthetic. Tamoxifen, a synthetic compound also a competitive inhibitor to growth enhancing tissue, functions as a selective estrogen receptor modulator (SERM), effectively competing with naturally synthesized estrogen in breast tissue. By inhibiting estrogen’s ability to bind to its receptor, tamoxifen reduces the hormone’s proliferative influence on hormone receptor-positive breast cancer cells. However, over time, this strategy has revealed a paradox.
While tamoxifen and related therapies have improved survival rates, prolonged use has been associated with significant side effects and, in some cases, resistance or secondary malignancies. In the long run even the estrogen therapy revealed its side effects like a double-edged sword. The above paradox of the estrogen therapy is to be monitored since excess estrogen both in Premenopausal and postmenopausal stages/ages is detrimental. The dietary restrictions of sugar cholesterol and Omega 6 EFAs also offset the estrogen paradox. Alternative Phyto nutrient or prevent prolonging the patient’s overall survival.
Keywords:Estrogen Cancer Paradox; Breast Cancer; Tumors
Abbreviations:SERM: Selective Estrogen Receptor Modulator
Introduction
Clinical studies consistently demonstrate the complex and sometimes contradictory role of estrogen in breast cancer development and treatment. The use of hormone therapy, although once hailed as revolutionary, remains largely empirical. Misguided manipulation of steroid hormones has historically contributed to conditions such as endometrial hyperplasia, endometriosis, and even renal tumors. Excess estrogen, whether endogenously produced or externally influenced, poses risks in both premenopausal and postmenopausal women. Hence, careful monitoring and individualized treatment strategies are essential. In addition to pharmacological interventions, lifestyle and dietary factors play a vital role in managing breast cancer.
Nutritional modifications, such as reducing the intake of refined sugars, cholesterol, and pro-inflammatory omega-6- EFAs, can help modulate estrogen levels and potentially counteract some of the adverse effects associated with hormonal therapies. The integration of alternative phytonutrients-plant-derived compounds with estrogen-modulating and anti-cancer properties-also holds promise in supporting long-term disease control.
Historical Observations and Experimental Studies
The relationship between estrogen and breast cancer was first observed in 1932 when estrone injections into male mice led to the development of mammary tumors Cresenjit [1]. Similarly, in ovariectomized rats, estrogen administration reactivated previously regressed tumors-mirroring observations in postmenopausal women with extra-ovarian estrogen synthesis. In rodent models induced with carcinogens like DMBA, tumor reactivation persisted despite ovary removal, implicating adrenal and peripheral estrogen sources. Surgical ablation of endocrine organs (ovaries, adrenals, hypophysis) was once considered a palliative treatment Pearson et al. [2].
Contradictory Findings in Human and Animal Studies
While estrogen reactivates tumors in rats, similar stimulation was not consistently observed in human breast cancer cases. Nonetheless, estrogens, prolactin, and other hormones have shown varying degrees of tumor-promoting effects, including the upregulation of Cathepsin-D and increased cell proliferation metrics like DNA ploidy and S-phase fraction. Stanton et al. [3] introduced a less invasive alternative-chemical adrenalectomy using aminoglutethimide and hydrocortisone..
Tumor Biology and Therapeutic Resistance
Tumor progression is often sustained by unrestricted synthesis of growth factors, enzymes (e.g., Cathepsin-D), and ectopic hormones such as β-hCG. Therapeutic strategies focusing on restricting key nutrients (e.g., isoleucine, glutamine), increasing intracellular cAMP, or employing prostaglandin analogs (e.g., PGE1) could suppress tumor cell proliferation.
Prognostic Factors Include:
i. Age (better prognosis post-menopause)
ii. Lymph node involvement
iii. Tumor size and invasiveness
iv. Cellular and nuclear morphology
v. Presence of necrosis and angiogenesis
vi. Chromosomal abnormalities and drug-resistance genes
(e.g., mdr-1)
Hormonal Receptor Status and Targeted Therapy
Patients with ER/PR-positive tumors benefit from antiestrogen therapies such as Tamoxifen. However, Tamoxifen carries side effects: thrombocytopenia, leukopenia, hypercalcemia, visual disturbances, and more Melby [4]. Similarly, glucocorticoids like prednisone and prednisolone are used in breast cancer therapy, albeit with systemic complications.
Limitations of Conventional Therapy
Traditional therapies-chemotherapy, radiation, and surgeryoften lead to temporary remission. Many patients relapse due to intrinsic tumor resistance and survival adaptations. As a result, modern cancer care risks becoming an economically burdensome yet marginally effective pursuit.
Role of Phytochemicals and Natural Agents
Natural compounds may provide safer, multi-targeted
therapies. Papaya, for example, contains sulfur compounds and
Omega-3 fatty acids that suppress estrogen synthesis and tumor
regrowth. Other beneficial substances include:
• Curcumin (turmeric): Affects multiple signaling
pathways Gupta et al. & Ballinda et al. [5,6]
• Iso-thiocyanates: Cytotoxic to hormone-driven cancers
• Lycopene (tomatoes, guava, watermelon): Induces
apoptosis, reduces metastasis (Cancer Letters, 2008)
• Bromelain (pineapple): Anti-cancer effects on breast
and uterine tissues
• Green/White tea (EGCG): Inhibits histone deacetylases
and induces cell death
• Broccoli: Contains β-carotene, sulforaphane, indoles,
etc.
Diet, Lifestyle, and Immune Function
Estrogen synthesis correlates with dietary cholesterol, particularly from red meat. Fish (e.g., salmon, tuna) and soy-based foods help reduce LDL, increase HDL, and suppress hormone synthesis. Fiber-rich diets aid in gastrointestinal cancer prevention by reducing polyp formation and binding carcinogens. A fortified immune system- via intake of vitamins (A, C, E, B-complex), and minerals (Zn, Se, Fe)-is essential for cancer prevention [7,8]..
The Estrogen Paradox
The “Estrogen Paradox” highlights the dual role of estrogen in both preventing and promoting breast cancer. Really the estrogen paradox is also evidenced by the reports that triple negative cancer cells also bind with the synthetic estrogens. It also infers the adaptive gene modulation in negative cells. That is the cells do not want to die due to harsh chemotherapy. So, these cells could have synthesized the ER receptors with intention to bind the natural estrogens and to proliferate. It is a paradox on the part of triple negative breast cancer cells (9). For instance, short-term estrogen replacement therapy (ERT) may reduce risk, whereas long-term use increases it (Nurses’ Health Study; Million Women Study) [10].
Estrogen-induced apoptosis involves:
a. Fas/FasL receptor activation
b. Mitochondrial cytochrome C release
c. BCL-2 modulation
d. Downregulation of NF-κB
Conversely, estrogen can stimulate carcinogenesis via:
a. Accelerated cell division
b. DNA mutation and repair inhibition
c. Direct genotoxicity
Conclusion
Despite decades of research, estrogen’s role in breast cancer remains complex and context dependent. While anti-estrogens like Tamoxifen provide some benefit, side effects and tumor resistance challenge their long-term efficacy. Phytochemicals and dietary modifications offer promising adjunctive strategies. Ultimately, a multidisciplinary, integrative approach that combines conventional treatment with evidence-based alternative medicine may offer the best path forward.
References
- Cresenjit L (1923) First estrogen-induced male mouse breast cancer study. J Exp Med 55(12): 123-130.
- Pearson OH, Elson VC, Rosenthal HE (1955) Effects of estrogen on breast cancer patients post-ovariectomy. J Clin Endocrinol Metab 15: 234-241.
- Stanton MF, Biskind GR, Biskind M (1977) Chemical adrenalectomy in breast cancer therapy. Cancer Res 37: 4054-4059.
- Melby JC (1977) Complications of corticosteroids. Ann Intern Med 87: 569-576.
- Gupta SC, Patchva S, Koh W, Aggarwal BB (2010) Discovery of curcumin, a component of golden spice, and its miraculous biological activities. Clin Exp Pharmacol Physiol 37: 47-53.
- Ballinda B, Amara VR, Chen H (2013) Curcumin and triple-negative breast cancer: an overview. Cancer Biol Ther 14: 1026-1035.
- Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10(8): 789-799.
- Cancer Letters (2008) Papaya-induced apoptosis and metastasis inhibition in breast cancer. Cancer Lett 265: 187-194.
- Nurses’ Health Study and Million Women Study (2003) Estrogen use and breast cancer risk. Lancet 362(9382): 419-427.
