Estetrol Combined to Progestogen for Menopause or Contraception Indication Is Neutral on Breast Cancer

Given the unequivocal benefits of menopause hormone therapies (MHT) and combined oral contraceptives (COC), there is a clinical need for new formulations devoid of any risk of breast cancer promotion. Accumulating data from preclinical and clinical studies support that estetrol (E4) is a promising natural estrogen for MHT and COC. Nevertheless, we report here that E4 remains active on the endometrium, even under a dose that is neutral on breast cancer growth and lung metastasis dissemination. This implies that a progestogen should be combined with E4 to protect the endometrium of non-hysterectomized women from hyperplasia and cancer. Through in vivo observations and transcriptomic analyses, our work provides evidence that combining a progestogen to E4 is neutral on breast cancer growth and dissemination, with very limited transcriptional impact. The assessment of breast cancer risk in patients during the development of new MHT or COC is not possible given the requirement of long-term studies in large populations. This translational preclinical research provides new evidence that a therapeutic dose of E4 for MHT or COC, combined with progesterone or drospirenone, may provide a better benefit/risk profile towards breast cancer risk compared to hormonal treatments currently available for patients.

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Inhibition of in vivo breast cancer growth by antisense oligodeoxynucleotides to type I insulin-like growth factor receptor mRNA involves inactivation of ErbBs, PI-3K/Akt and p42/p44 MAPK signaling pathways but not modulation of progesterone receptor activity

Oncogene ◽

10.1038/sj.onc.1207659 ◽

2004 ◽

Vol 23 (30) ◽

pp. 5161-5174 ◽

Cited By ~ 46

Author(s):

Mariana Salatino ◽

Roxana Schillaci ◽

Cecilia J Proietti ◽

Romina Carnevale ◽

Isabel Frahm ◽

...

Keyword(s):

Breast Cancer ◽

Growth Factor Receptor ◽

Mapk Signaling ◽

Antisense Oligodeoxynucleotides ◽

Cancer Growth ◽

Type I ◽

Receptor Mrna ◽

Breast Cancer Growth ◽

Mapk Signaling Pathways

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No association of TP53 codon 72 and intron 3 16-bp duplication polymorphisms with breast cancer risk in Chinese Han women: new evidence from a population-based case–control investigation

European Journal of Medical Research ◽

10.1186/s40001-018-0345-6 ◽

2018 ◽

Vol 23 (1) ◽

Cited By ~ 3

Author(s):

Weiming Hao ◽

Xia Xu ◽

Haifeng Shi ◽

Chiyu Zhang ◽

Xiaoxiang Chen

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Population Based ◽

Case Control ◽

Chinese Han ◽

Codon 72 ◽

New Evidence

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IL-1 drives breast cancer growth and bone metastasis in vivo

Oncotarget ◽

10.18632/oncotarget.12289 ◽

2016 ◽

Vol 7 (46) ◽

pp. 75571-75584 ◽

Cited By ~ 71

Author(s):

Ingunn Holen ◽

Diane V. Lefley ◽

Sheila E. Francis ◽

Sarah Rennicks ◽

Steven Bradbury ◽

...

Keyword(s):

Breast Cancer ◽

Bone Metastasis ◽

Cancer Growth ◽

Breast Cancer Growth

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Estrogen Deprivation and Inhibition of Breast Cancer Growth in Vivo through Activation of the Orphan Nuclear Receptor Liver X Receptor

Molecular Endocrinology ◽

10.1210/me.2007-0187 ◽

2007 ◽

Vol 21 (8) ◽

pp. 1781-1790 ◽

Cited By ~ 81

Author(s):

Haibiao Gong ◽

Ping Guo ◽

Yonggong Zhai ◽

Jie Zhou ◽

Hirdesh Uppal ◽

...

Keyword(s):

Breast Cancer ◽

Liver X Receptor ◽

Cancer Growth ◽

Estrogen Metabolism ◽

Endocrine Disorders ◽

Estrogen Deprivation ◽

Uterine Epithelial Cell ◽

Hepatic Expression ◽

Breast Cancer Growth

Abstract Estrogen plays an important role in normal physiology. It is also a risk factor for breast cancer, and antiestrogen therapies have been shown to be effective in the treatment and prevention of breast cancers. The liver is important for estrogen metabolism, and a compromised liver function has been linked to hyperestrogenism in patients. In this report, we showed that the liver X receptor (LXR) controls estrogen homeostasis by regulating the basal and inducible hepatic expression of estrogen sulfotransferase (Est, or Sult1e1), an enzyme critical for metabolic estrogen deactivation. Genetic or pharmacological activation of LXR resulted in Est induction, which in turn inhibited estrogen-dependent uterine epithelial cell proliferation and gene expression, as well as breast cancer growth in a nude mouse model of tumorigenicity. We further established that Est is a transcriptional target of LXR, and deletion of the Est gene in mice abolished the LXR effect on estrogen deprivation. Interestingly, Est regulation by LXR appeared to be liver specific, further underscoring the role of liver in estrogen metabolism. Activation of LXR failed to induce other major estrogen-metabolizing enzymes, suggesting that the LXR effect on estrogen metabolism is Est specific. In summary, our results have revealed a novel mechanism controlling estrogen homeostasis in vivo and may have implications for drug development in the treatment of breast cancer and other estrogen-related cancerous endocrine disorders.

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