Lower-Dose vs High-Dose Oral Estradiol Therapy of Hormone Receptor–Positive, Aromatase Inhibitor–Resistant Advanced Breast Cancer

Ellis, Matthew J.; Gao, Feng; Dehdashti, Farrokh; Jeffe, Donna B.; Marcom, P. Kelly; Carey, Lisa A.; Dickler, Maura N.; Silverman, Paula; Fleming, Gini F.; Kommareddy, A.; Jamalabadi-Majidi, Shohreh; Crowder, Robert J.; Siegel, Barry A.

doi:10.1001/jama.2009.1204

Cited by 260 publications

(242 citation statements)

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“…This pro-apoptotic process involves both intrinsic and extrinsic death pathways and most recently has been shown to involve AMPK and its downstream targets FoxO3, Fas ligand, Gadd 45a, and BIM (Chen et al 2015). Several studies demonstrate objective tumor regressions, often prolonged, in women receiving exogenous oestrogen (Ellis et al 2009, Lonning 2009). This proapoptotic pathway may also explain why oestrogen used alone without a concomitant progestin in the Women's Health Initiative (WHI) study caused a paradoxical reduction in breast cancer in women lacking a uterus (Anderson et al 2012).…”

Section: Clinical Therapeutic Aspects Of Oestrogensmentioning

confidence: 99%

Celebrating 75 years of oestradiol

Simpson

Santen

2015

Journal of Molecular Endocrinology

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Oestrogens exert important effects on the reproductive as well as many other organ systems in both men and women. The history of the discovery of oestrogens, the mechanisms of their synthesis, and their therapeutic applications are very important components of the fabric of endocrinology. These aspects provide the rationale for highlighting several key components of this story. Two investigators, Edward Doisy and Alfred Butenandt, purified and crystalized oestrone nearly simultaneously in 1929, and Doisy later discovered oestriol and oestradiol. Butenandt won the Nobel Prize for this work and Doisy's had to await his purification of vitamin K. Early investigators quickly recognized that oestrogens must be synthesized from androgens and later investigators called this process aromatization. The aromatase enzyme was then characterized, its mechanism determined, and its structure identified after successful crystallization. With the development of knock-out methodology, the precise effects of oestrogen in males and females were defined and clinical syndromes of deficiency and excess described. Their discovery ultimately led to the development of oral contraceptives, treatment of menopausal symptoms, therapies for breast cancer, and induction of fertility, among others. The history of the use of oestrogens for postmenopausal women to relieve symptoms has been characterized by cyclic periods of enthusiasm and concern. The individuals involved in these studies, the innovative thinking required, and the detailed understanding made possible by evolving biologic and molecular techniques provide many lessons for current endocrinologists. Discovery of oestrogenThe concept that substances secreted by one organ could then be transported internally to another via the blood stream is the underpinning of the field of endocrinology. The 'father of physiology', Claude Bernard, articulated the concept of internal secretion by describing how the liver produces glucose, which then travels to and is utilized by other tissues in the body. This concept underlies studies on the ovaries, which became a focus of investigation later in the century. In 1896, Emil Knauer, a 29-year-old Austrian, excised the ovaries of adult rabbits and then re-implanted pieces into different locations in the same animals (Watkins 2007 Doisy then enlisted a nurse in the obstetrics clinic to supply each pregnant patient with a 1 gal jug and ask for her urine. This provided the needed material but was fraught with difficulties. Suspected to be a bootlegger because of the large jugs of yellow material in his car, one of Doisy's drivers was nearly arrested until he suggested using the sniff test with the response 'My god, it is urine'. Doisy, then being recruited to St Louis University, continued his efforts to purify the active substance. Each extract was tested with a bioassay and its effect on uterine stimulation. Urine, the material of choice for study, was initially extracted with a very large countercurrent apparatus (Fig. 1). Costing the exorbitan...

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Section: Clinical Therapeutic Aspects Of Oestrogensmentioning

confidence: 99%

Celebrating 75 years of oestradiol

Simpson

Santen

2015

Journal of Molecular Endocrinology

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“…There were 4 of 32 complete responses, and one patient maintained a complete response for an additional 7 y, even after stopping estrogen (27). 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).…”

mentioning

confidence: 98%

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.

144

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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“…Estradiol has been shown that has a role in cancer treatment. [6] In women with advanced breast cancer and acquired resistance to aromatase inhibitors, a daily dose of 6 mg of estradiol provided a similar clinical benefit rate as 30 mg, with fewer serious adverse events [7]. However, there are studies showing that estrogens may have carcinogenic effects.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis in Colon Cancer (HT29) Cells Exposed to Estradiol Valerat

2017

Dec. 4-6, 2017 London (UK) ICEEET-2017, ICABES-2017, ICCATE-2017, ICLSSE-17 &Amp; LBMCSR-2017

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Lower-Dose vs High-Dose Oral Estradiol Therapy of Hormone Receptor–Positive, Aromatase Inhibitor–Resistant Advanced Breast Cancer

Cited by 260 publications

References 14 publications

Celebrating 75 years of oestradiol

Celebrating 75 years of oestradiol

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

Apoptosis in Colon Cancer (HT29) Cells Exposed to Estradiol Valerat

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