Effect of Long-Term Estrogen Deprivation on Apoptotic Responses of Breast Cancer Cells to 17 -Estradiol

Song, Robert X.-D.; Mor, Gil; Naftolin, F.; McPherson, R. A.; Song, J. J.; Zhang, Zhenguo; Yue, Wei; Wang, JiPing; Santen, Richard J.

doi:10.1093/jnci/93.22.1714

Cited by 273 publications

(283 citation statements)

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“…However, the MCF-7 cell line has accurately predicted clinical responses to antihormonal therapy in breast cancer (35). We and others have reported antihormonal-resistant MCF-7-based models besides 5C cells that exhibit E 2 -induced apoptosis in vitro and in vivo (18,19,23,36). We are aware of only one other breast cancer model not derived from MCF-7 cells that exhibits this behavior (i.e., T47D cells stably expressing PKCα), but only when grown in vivo as xenograft tumors (37).…”

Section: Resultsmentioning

confidence: 99%

“…When cells were grown under long-term estrogendeprived conditions (>1 y), cells lost their dependency on estrogen for proliferation but maintained expression of ER. Subsequent studies of E 2 action on the growth of long-term estrogen-deprived MCF-7 cells in vitro at high (23) and low concentrations in vitro and in vivo (24,25) indicated that the concept of "an estrogen purge" (19) to destroy antihormone-resistant cells could be applied to the treatment of breast cancer. This concept has now been translated to clinical trials.…”

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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.

146

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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Section: Resultsmentioning

confidence: 99%

mentioning

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.

146

190

View full text Add to dashboard Cite

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“…To advance this idea, it would be valuable to examine whether the observations in the laboratory with the evolution of tamoxifen drug resistance apply to other SERMs and to breast cancer cells that have adapted to oestrogen deprivation, that is, as an expression of resistance to aromatase inhibitors. Song et al (2001) were the first to demonstrate that oestradiol causes apoptosis in breast cancer cells that have been adapted to grow in an oestrogen-free environment for prolonged periods. These investigators suggested that their data provided an explanation for the effectiveness of high-dose diethylstilboestrol formally used to treat breast cancer in elderly postmenopausal women, that is, women who were 10 -25 years after menopause.…”

Section: Changes In the Understanding Of Antihormone Resistancementioning

confidence: 99%

“…However, it is the remarkable switch from oestrogen-stimulated growth in breast cancer to oestrogenstimulated death that merits investigation. Song et al (2001) first focused attention on the fas, fas ligand pathway as a potential mechanism of oestrogen-induced apoptosis in oestrogen-deprived breast cancer cells. Study of molecular mechanisms for oestrogeninduced tumour regression have recently been extended with the demonstration that oestrogen simultaneously collapses survival mechanisms (HER2/neu NFkB) in the Phase II SERM-resistant tumour, and enhances the expression of the fas receptor Osipo et al, 2003) ( Figure 3C, D).…”

Section: Molecular Mechanismsmentioning

confidence: 99%

Targeting oestrogen to kill the cancer but not the patient

2004

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The link between sex steroids and the development and growth of breast cancer has proved to be an invaluable clue for advances in the prevention and treatment of breast cancer. The identification of the oestrogen receptor (ER) not only allowed advances in the molecular endocrinology of oestrogen action, but also provided a target for antioestrogenic therapeutic agents. However, the application of long-term or indefinite treatment regimens has consequences for the breast cancer. New forms of resistance, based upon enhanced cellular survival networks independent of ER and the suppression of apoptotic mechanisms, develop and then evolve. Remarkably, low concentrations of oestrogen collapse survival pathways and induce apoptosis in completely antihormonally refractory breast cancer. However, recurrent oestrogen-stimulated disease is again sensitive to antihormonal therapy. The novel reapplication of the ER as a therapeutic target for apoptosis is emerging as a new strategy for the long-term targeted maintenance treatment of breast cancer, and in formulating a targeted strategy for endocrine independent cancer. British Journal of Cancer (2004) There is an expanding clinical database that implicates oestrogen and progestins (hormone replacement therapy, HRT) in the development and growth of breast cancer. Evidence to support this conclusion comes from two major clinical sources: clinical studies of HRT, initially designed to determine the benefits of replacement approaches on postmenopausal women's health (Writing Group for the Women's Health Initiative Investigators, 2002; Million Women Study Collaborators, 2003) and the successful clinical strategy of treating breast cancer by blocking oestrogen action.The Million Woman Study provides powerful (Million Women Study Collaborators, 2003) information about the actual impact of HRT on the incidence of breast cancer. A total of 1 084 110 UK women aged 50 -64 years were recruited to determine the association of HRT use with breast cancer incidence and death.

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“…Despite the initial benefits of tamoxifen, most patients eventually relapsed ( Figure 2). Furthermore, such tamoxifen-resistant tumours may be stimulated by tamoxifen and, in contrast, suppressed by oestrogens (Song et al, 2001). This potentially might be exploited for 'withdrawal' therapy in breast cancer.…”

Section: Antihormonal Therapy In Breast Cancermentioning

confidence: 99%

Tissue-selective therapy of cancer

2003

Br J Cancer

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Effect of Long-Term Estrogen Deprivation on Apoptotic Responses of Breast Cancer Cells to 17 -Estradiol

Abstract: Tumor regression induced by high-dose estrogen therapy in postmenopausal woman may result from estrogen activation of Fas-mediated apoptosis.

Cited by 273 publications

References 33 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

Targeting oestrogen to kill the cancer but not the patient

Tissue-selective therapy of cancer

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