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Effects of estrogen on breast cancer development: Role of estrogen receptor independent mechanisms
Open accessAbstract
Development of breast cancer involves genetic factors as well as lifetime exposure to estrogen. The precise molecular mechanisms whereby estrogens influence breast tumor formation are poorly understood. While estrogen receptor α (ERα) is certainly involved, nonreceptor mediated effects of estradiol (E2) may also play an important role in facilitating breast tumor development. A “reductionist” strategy allowed us to examine the role of ERα independent effects of E2 on mammary tumor development in ERα knockout (ERKO) mice bearing the Wnt‐1 oncogene. Exogenous E2 “clamped” at early follicular and midluteal phase levels (i.e., 80 and 240 pg/ml) accelerated tumor formation in a dose‐related fashion in ERKO/Wnt‐1 animals (p = 0.0002). Reduction of endogenous E2 by oophorectomy (p < 0.001) or an aromatase inhibitor (AI) (p = 0.055) in intact ERKO/Wnt‐1 animals delayed tumorigenesis as further evidence for an ER‐independent effect. The effects of residual ERα or β were not involved since enhancement of tumor formation could not be blocked by the antiestrogen fulvestrant. 17α‐OH‐E2, a metabolizable but ER‐impeded analogue of E2 stimulated tumor development without measurable uterine stimulatory effects. Taken together, our results suggest that ER‐independent actions of E2 can influence breast tumor development in concert with ER dependent effects. These observations suggest 1 mechanism whereby AIs, which block E2 synthesis, would be more effective for breast cancer prevention than use of antiestrogens, which only block ER‐mediated effects.
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“E2 in breast tissue is not associated with protective metabolic effects, but rather has been linked to proliferative tumor growth (195).”
From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [195]
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“Elevated aromatase expression in breast WAT increases local E2 production, which may contribute to estrogen receptor-positive (ER+) breast cancer pathogenesis (135, 195, 196).”
From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [195]
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Simu, S., Marcovici, I., Dobrescu, A., Malita, D. C., Dehelean, C. A., Coricovac, D. E., Olaru, F., Drăghici, G. A., & Navolan, D. B. (2021) · Molecules · doi:10.3390/molecules26092776 · Cited by 33
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BackgroundNutrition Intervention and Microbiome Modulation in the Management of Breast Cancer
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“In addition, in this study clinical impact of 17βHSD1 was much higher than that of ERβ (Table 3) suggesting that E2 may also have some other important functions besides ERβ mediated actions in NSCLCs, as suggested by earlier studies in breast cancer [24].”
ResultEstradiol increases ER-negative breast cancer metastasis in an experimental model
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“Epidemiologic and experimental data implicate E2 as an important factor contributing to BC carcinogenesis (2).”
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“…et al. 2018; Antoniou and Easton 2006) and in this respect, there are some genes with pivotal functions, for example, connexin 37, a tumor inhibitor, and ABCB1, CYP1B1, and CDKN2A/B associated with BC susceptibility (Zeliha et al. 2020; Hesari et al. 2019; Yue et al. 2010; Kontzoglou et al. 2013).”
BackgroundVidafar, P., & Spitschan, M. (2022) · Journal of Biological Rhythms · doi:10.1177/07487304221126785 · Cited by 16
“Estradiol has been shown to play a role in the development of breast tumors (Cauley et al., 1999; Hayashi et al., 2003; Sasano et al., 2006; Yue et al., 2010), whereas melatonin has been shown to have anticarcinogenic properties (Karbownik et al., 2001; Srinivasan et al., 2008), reducing the…”
BackgroundWang, C., Guo, D., You, T., Shen, D.-W., Wang, C., Tang, L., WANG, J., Xu, R., & Zhang, H. (2014) · Molecular Medicine Reports · doi:10.3892/mmr.2014.2595 · Cited by 15
“Fulvestrant is an anti-estrogen drug which causes blockade of residual ER α and ER β in breast cells (19).”
Self-citationEstradiol modulated colorectal cancer stem cells bioactivity and interaction with endothelial cells
Zamani, A. R. N., Avcı, Ç. B., Ahmadi, M., Pouyafar, A., Bagheri, H. S., Fathi, F., Heidarzadeh, M., Rezaie, J., Mirhosseini, Y., Saberianpour, S., et al. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118078 · Cited by 15
Menopause Is More Than Just Loss of Fertility
Baker, C., & Benayoun, B. A. (2023) · Public Policy & Aging Report · doi:10.1093/ppar/prad023 · Cited by 19
Pellikaan, K., Nguyen, N., Rosenberg, A. G. W., Coupaye, M., Goldstone, A. P., Höybye, C., Markovic, T., Grugni, G., Crinò, A., Caixàs, A., et al. (2023) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgad312 · Cited by 12
Dell’Acqua, G., Richards, A., & Thornton, M. J. (2020) · Nutrients · doi:10.3390/nu12113537 · Cited by 13
“This is further supported by data confirming that bilateral oophorectomy in women under 35 years of age reduces the lifetime risk by 75% [5].”
BackgroundMethodInfluentialKarakaş, B., Aka, Y., Giray, A., Temel, Ş. G., Acikbas, U., Başağa, H., Gül, Ö., & Kütük, Ö. (2021) · Cell Death Discovery · doi:10.1038/s41420-021-00573-2 · Cited by 13
Anti-cancer and Biotherapeutic Potentials of Probiotic Bacteria
Hassan, Z. (2019) · Journal of Cancer Science & Therapy · doi:10.4172/1948-5956.1000575 · Cited by 14
“Oestrogen is hypothesized to influence breast cancer mediated through estrogen receptor α as well as estradiol, but the mechanism is poorly understood [21].”
Risk of Osteoporotic Fracture in Patients with Breast Cancer: Meta-Analysis
Lee, S., Yoo, J., Lee, Y., Park, J.-W., Won, S., Yeom, J.-U., Im, J. W., Lim, S. M., Ha, Y., & Koo, K. (2020) · Journal of Bone Metabolism · doi:10.11005/jbm.2020.27.1.27 · Cited by 12
Endocrine disrupting chemicals (EDCs) and sex steroid receptors
Hall, J. M., & Korach, K. S. (2021) · Advances in pharmacology · doi:10.1016/bs.apha.2021.04.001 · Cited by 12
Self-citationRoles of lncRNAs related to the p53 network in breast cancer progression
Song, J., Cui, Q., & Gao, J. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1453807 · Cited by 10
“6 ) Hormonal Factors: Estrogen, for instance, promotes the proliferation of breast epithelial cells, potentially increasing the risk of mutations during cell division (26).”
BackgroundApplication of the Key Characteristics of Carcinogens to Bisphenol A
Ricker, K., Cheng, V., Hsieh, C., Tsai, F. C., Osborne, G., Li, K., Yilmazer-Musa, M., Sandy, M. S., Cogliano, V. J., Schmitz, R., et al. (2024) · International Journal of Toxicology · doi:10.1177/10915818231225161 · Cited by 11
“302 BPA ’ s effects may be ampli fi ed or enhanced by estrogenic BPA metabolites, such as MBP and HCA.”
BackgroundOncologic manifestations of Klinefelter syndrome
Rojas, A. P., Vo, D. V., Mwangi, L., Rehman, S., & Peiris, A. N. (2020) · HORMONES · doi:10.1007/s42000-020-00241-7 · Cited by 11
3. Mechanisms Relating Estrogens to Breast Cancer
Yager, J. D., & Santen, R. J. (2012) · Translational endocrinology & metabolism · doi:10.1210/team.9781936704064.ch3 · Cited by 11
Self-citationOvarian stimulation for fertility treatments and risk of breast cancer: a matched cohort study
Machtinger, R., Fallach, N., Goldstein, I., Chodick, G., Schiff, E., Orvieto, R., & Mashiach, R. (2021) · Human Reproduction · doi:10.1093/humrep/deab270 · Cited by 11
Xu, T., Liu, K., Zhang, Y., Chen, Y., & Yin, D. (2024) · Environmental Science and Pollution Research · doi:10.1007/s11356-024-33872-z · Cited by 10
“Females are particularly vulnerable to the health impacts of endocrine-disrupting chemicals, as inappropriate regulation of estrogen has been linked to female-specific cancers, including breast and uterine cancer (Yue et al. 2010).”
Peters, M. D. J., Ramsey, I., Kennedy, K. J., Sharplin, G. R., & Eckert, M. C. (2021) · Journal of Advanced Nursing · doi:10.1111/jan.15094 · Cited by 10
Manyonda, I., Talaulikar, V. S., Pirhadi, R., Ward, J. H., Banerjee, D., & Onwude, J. L. (2022) · Journal of Clinical Medicine Research · doi:10.14740/jocmr4646 · Cited by 10
“Traditionally, it has been thought that estrogens could play an important role in the pathophysiology of breast cancer, firstly because the female breast contains an abundance of estrogen receptors, and secondly because of the observation that estrogens can aggravate estrogen receptor-positive breast cancer [1].”
BackgroundArecco, L., Cacilhas, P. M., Gismondi, C. B. L., Bruzzone, M., Gentile, G., Gerosa, R., Blondeaux, E., Agostinetto, E., Dauccia, C., Lobo-Martins, S., et al. (2026) · The Breast · doi:10.1016/j.breast.2026.104719 · Cited by 9
“Finally, alcohol intake ele-vates circulating estrogen levels [57,58], which is particularly relevant for the development of hormone receptor-positive BC [59].”
Lan, J., Gao, X. H., & Kaul, R. (2019) · EXCLI journal · doi:10.17179/excli2019-1541 · Cited by 9
“Estrogen has been reported to be involved in normal cell physiology as well as malignancies (Yue et al., 2010; Chen et al., 2018; Ito et al., 2001).”
Backgroundde Souza, V. G., Bandeira, L. B., Souza, N. C. S. E., Taboga, S. R., Martins, T. M. M., & Perez, A. P. S. (2021) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s2040174421000040 · Cited by 10
A conversation about hormone therapy: is there an appropriate dose, route, and duration of use?
(2017) · Menopause The Journal of The North American Menopause Society · doi:10.1097/gme.0000000000000986 · Cited by 10
Cáceres, S., Monsalve, B., Alonso‐Diez, Á., Crespo, B., Illera, M. J., de Andrés, P. J., Silván, G., & Illera, J. C. (2021) · Cancers · doi:10.3390/cancers13194967 · Cited by 8
“Other authors support this claim since they described that E2 can influence the development of breast cancer through mechanisms independent of ER [37].”
BackgroundAl-Ghamdi, A. R., Ahmed, W. U., Al-Wabli, R. I., Almutairi, M. S., & Rahman, A. F. M. M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26020833 · Cited by 11
Cohick, W. S., Crismale‐Gann, C., Stires, H., & Katz, T. A. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-09614-8_24 · Cited by 8
Exogenous estrogen protects mice from the consequences of obesity and alcohol
Holcomb, V. B., Hong, J., & Núñez, N. P. (2012) · Menopause The Journal of The North American Menopause Society · doi:10.1097/gme.0b013e31823cf6ee · Cited by 8
Breast cancer in schizophrenia could be interleukin-33-mediated
Borovčanin, M., & Vesić, K. (2021) · World Journal of Psychiatry · doi:10.5498/wjp.v11.i11.1065 · Cited by 8
Wang, Y., Tan, S., Pan, E., Ma, Y., Wu, X., Yu, Z., & Jiang, K. (2022) · OncoTargets and Therapy · doi:10.2147/ott.s363856 · Cited by 8
Oestrogen receptor-independent actions of oestrogen in cancer
Gopinath, P., Oviya, R. P., & Gopisetty, G. (2023) · Molecular Biology Reports · doi:10.1007/s11033-023-08793-8 · Cited by 7
“However, the use of letrozole in combination with a minimally active form of E2 delayed tumour formation, even in animals with intact ovaries [27, 28].”
BackgroundShinde, P., Shete, A. S., Ghorpade, V. S., Harale, N. S., Patil, S. S., Desai, N., & Patil, S. (2025) · Journal of Pharmaceutical Innovation · doi:10.1007/s12247-025-09956-9 · Cited by 7
“This can be achieved by blocking the binding of estrogen receptors to their specific ligands or by disrupting estrogen production through modifications in aromatase gene expression or enzyme activity [4].”
Jalilvand, A., Yari, K., Aznab, M., Rahimi, Z., Far, I. S., & Mohammadi, P. (2020) · Journal of Clinical Laboratory Analysis · doi:10.1002/jcla.23529 · Cited by 7
Incidence of Breast Cancer and Enterococcus Infection: A Retrospective Analysis
Cardeiro, M., Ardeljan, A., Frankel, L. R., Kim, E., Takabe, K., & Rashid, O. M. (2023) · World Journal of Oncology · doi:10.14740/wjon1551 · Cited by 7
“BC is often a hormonally driven malignancy with estrogen playing an essential role [28, 29].”
BackgroundReview Article: Understanding the Role of the Microbiome in Breast Cancer Progression
Kumari, S., Srilatha, M., & Nagaraju, G. P. (2025) · Critical Reviews™ in Oncogenesis · doi:10.1615/critrevoncog.2024056468 · Cited by 6
Thonusin, C., Pantiya, P., Jaiwongkam, T., Kerdphoo, S., Arunsak, B., Amput, P., Palee, S., Pratchayasakul, W., Chattipakorn, N., & Chattipakorn, S. C. (2020) · Menopause The Journal of The North American Menopause Society · doi:10.1097/gme.0000000000001586 · Cited by 6
“It has also been acknowledged that ET can cause fatal adverse effects, such as thromboembolism, breast cancer, and endometrial cancer, especially in elderly or obese women.(68-73) Therefore, exogenous estrogen alone may not be an appropriate option for the treatment of hyperlipidemia in postmenopausal women.”
BackgroundPetre, I., Sirbu, D. T., Petrita, R., Toma, A.-D., Peta, E., & Dimcevici‐poesina, F. (2023) · Biomedical Reports · doi:10.3892/br.2023.1618 · Cited by 6
“Exposure to high levels of estrogen is also linked to an increased risk of breast cancer (15).”
Low-grade papillary adenocarcinoma of minor salivary glands in pregnancy
Prabhu, R. V., Dinkar, A., Spadigam, A., & Prabhu, V. D. (2015) · Indian Journal of Cancer · doi:10.4103/0019-509x.178438 · Cited by 6
Metadata
- Authors
- Yue, W., Wang, J., Li, Y., Fan, P., Liu, G., Zhang, N., Conaway, M., Wang, H., Korach, K. S., Bocchinfuso, W., & Santen, R.
- Affiliations
- University of Virginia Health System (US)
- National Institutes of Health (US)
- Corresponding author
- Yue, Wei
- ORCID
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2010-08-20
- Volume
- 127
- Issue
- 8
- Pages
- 1748-1757
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- PMC
- PMC4775086
- OpenAlex
- W2035185970
- Cited by
- 196
- References
- 73
- Citations by year
- 2026: 2 · 2025: 26 · 2024: 16 · 2023: 30 · 2022: 19 · 2021: 23 · 2020: 21 · 2019: 10 · 2018: 10 · 2017: 7 · 2016: 3 · 2015: 5 · 2014: 6 · 2013: 7 · 2012: 9
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Environmental Health Sciences (Z01ES070065)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Keywords
- breast cancer, estrogen receptor alpha, estrogen receptor beta, estradiol, ER knockout mice, aromatase inhibitors, oophorectomy, fulvestrant, breast cancer prevention, antiestrogens
- MeSH terms
- Fulvestrant, Letrozole, Animals, Antineoplastic Agents, Dose-Response Relationship, Drug, Estradiol, Estrogen Antagonists, Female, Humans, Mammary Neoplasms, Experimental, Mice, Transgenic, Nitriles, Ovariectomy, Triazoles, Mice, Knockout, Estrogen Receptor alpha, Cell Proliferation, Wnt1 Protein, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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