Influence of Synthetic Oestrogens on Advanced Malignant Disease

Haddow, Alexander; Watkinson, Jean M.; Paterson, Edith; Koller, P. C.

doi:10.1136/bmj.2.4368.393

Cited by 297 publications

(158 citation statements)

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“…The first successful chemical therapy for the treatment of any cancer was the use of high-dose synthetic estrogen for the treatment of metastatic breast cancer (3). Response rates for patients who were more than a decade beyond menopause were about 30%.…”

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confidence: 99%

“…A recent study in patients whose breast cancer had responded but then failed AI treatment (28) showed that low-dose E 2 treatment (6 mg daily) would produce the same clinical benefit as high-dose E 2 (30 mg daily) but with fewer toxic side effects. Thus, laboratory observations with low doses of estrogen treatment translate to clinical practice, and a mechanism is now emerging to explain the original observations by Haddow (3,4). The goal of future translational research is to discover molecular mechanisms to amplify the estrogen-induced apoptotic trigger.…”

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confidence: 99%

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Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time

Ariazi

Cunliffe

Lewis-Wambi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

147

190

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This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2009.Contributed by V. Craig Jordan, September 14, 2011 (sent for review June 21, 2011) In laboratory studies, acquired resistance to long-term antihormonal therapy in breast cancer evolves through two phases over 5 y. Phase I develops within 1 y, and tumor growth occurs with either 17β-estradiol (E 2 ) or tamoxifen. Phase II resistance develops after 5 y of therapy, and tamoxifen still stimulates growth; however, E 2 paradoxically induces apoptosis. This finding is the basis for the clinical use of estrogen to treat advanced antihormone-resistant breast cancer. We interrogated E 2 -induced apoptosis by analysis of gene expression across time (2-96 h) in MCF-7 cell variants that were estrogen-dependent (WS8) or resistant to estrogen deprivation and refractory (2A) or sensitive (5C) to E 2 -induced apoptosis. We developed a method termed differential area under the curve analysis that identified genes uniquely regulated by E 2 in 5C cells compared with both WS8 and 2A cells and hence, were associated with E 2 -induced apoptosis. Estrogen signaling, endoplasmic reticulum stress (ERS), and inflammatory response genes were overrepresented among the 5C-specific genes. The identified ERS genes indicated that E 2 inhibited protein folding, translation, and fatty acid synthesis. Meanwhile, the ERS-associated apoptotic genes Bcl-2 interacting mediator of cell death (BIM; BCL2L11) and caspase-4 (CASP4), among others, were induced. Evaluation of a caspase peptide inhibitor panel showed that the CASP4 inhibitor z-LEVD-fmk was the most active at blocking E 2 -induced apoptosis. Furthermore, z-LEVD-fmk completely prevented poly (ADP-ribose) polymerase (PARP) cleavage, E 2 -inhibited growth, and apoptotic morphology. The up-regulated proinflammatory genes included IL, IFN, and arachidonic acid-related genes. Functional testing showed that arachidonic acid and E 2 interacted to superadditively induce apoptosis. Therefore, these data indicate that E 2 induced apoptosis through ERS and inflammatory responses in advanced antihormone-resistant breast cancer.aromatase inhibitor | antihormonal resistance | estrogen receptor | gene expression microarrays | selective estrogen receptor modulator E lucidation of the basic structure function relationships of synthetic estrogens based on either stilbene (1) or triphenylethylene (2) was a landmark achievement that continues to have major therapeutic implications to this day. The first successful chemical therapy for the treatment of any cancer was the use of high-dose synthetic estrogen for the treatment of metastatic breast cancer (3). Response rates for patients who were more than a decade beyond menopause were about 30%. Importantly, treatment near menopause was ineffective, and therefore, tumor responsiveness was related to the duration of estrogen deprivation. In 1970, Alexander Haddow commented that "the extraordinary extent of tumor regression observed in...

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confidence: 99%

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confidence: 99%

Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time

Ariazi

Cunliffe

Lewis-Wambi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

147

190

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“…1). DES, a synthetic estrogen, was once thought to revolutionize estrogen therapy and was used to treat breast and prostate cancer with high-doses of the drug as standard endocrine therapy before the discovery of the anti-estrogens [8].…”

Section: Agonistsmentioning

confidence: 99%

Breast Cancer, Estrogen Receptor and Ligands

Bai

Gust²

2009

Archiv der Pharmazie

114

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This review emphasizes the relationship of breast cancer, estrogen receptor and ligands, especially the centrality of the estrogen receptor, which mediates on one hand the hormone-induced gene transcription and on the other hand the anti-estrogen action against breast cancer. The characterization of the estrogen receptor ligand-binding domain co-crystallized with agonists or antagonists provided a molecular basis to gain an insight into the regulation of estrogen receptor and, thereby, to describe the mechanism of the hormone therapy in treating breast cancer.

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“…first validation of an antitumour response in animal models and then a clinical trial. Sir Alexander Haddow FRS discovered [20] that high dose synthetic oestrogen treatment could produce a 30% response rate in breast cancer patients more than 5 years after their menopause [21]. This was the first chemical therapy to treat any cancer successfully and was proven in clinical trials.…”

Section: The Early Years Of the Tamoxifen Talementioning

confidence: 99%

Proven value of translational research with appropriate animal models to advance breast cancer treatment and save lives: the tamoxifen tale

Jordan

2015

Brit J Clinical Pharma

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Influence of Synthetic Oestrogens on Advanced Malignant Disease

Cited by 297 publications

References 2 publications

Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time

Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time

Breast Cancer, Estrogen Receptor and Ligands

Proven value of translational research with appropriate animal models to advance breast cancer treatment and save lives: the tamoxifen tale

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