Estrogen-induced apoptosis in a breast cancer model resistant to long-term estrogen withdrawal

Lewis, Joan S.; Osipo, Clodia; Meeke, Kathleen; Jordan, V. Craig

doi:10.1016/j.jsbmb.2004.12.032

Cited by 115 publications

(120 citation statements)

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“…Before gene expression microarray studies were carried out, the estrogen-dependent WS8 (29-31), ED-resistant but apoptosis-refractory 2A (25,30,31), and apoptosis-sensitive 5C cells (24,29,32) were characterized to confirm previously reported growth responses, biomarker status, and estrogen response element (ERE) -regulated transcriptional activity (SI Results and Discussion, SI Methods, and Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

“…By describing and defining these molecular events, refractory cells may be manipulated to respond to estrogen-induced apoptosis. To begin to address the question, we have developed a series of MCF-7 variants that are either estrogen-dependent for growth (MCF-7:WS8 cells) (29)(30)(31) or resistant to estrogen deprivation (ED) and refractory (MCF-7:2A) (25,30,31) or sensitive (MCF-7:5C) (24,29,32) to E 2 -induced apoptosis. We previously reported changes in gene expression among these cell lines by Affymetrix-based microarray analysis under estrogen-free conditions (33).…”

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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.

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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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.

144

190

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“…had responded to first-line hormonal therapy (Song et al 2001, Lewis et al 2005. The underlying basis for this approach is that long-term deprivation of oestrogen causes breast cancer cells to respond to exogenous oestrogen with apoptosis.…”

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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“…It is important to note that these observations were initially made with an estrogen-supersensitive clone of MCF-7 breast cancer cells (WS8) using only tamoxifen treatment for 5-10 years in vivo (17,18) and raloxifene-resistant model (19,20) in vitro and few weeks (20) or a year or two (19,20) in vivo. These data are not confined to SERM-resistant models as similar observations were made in long-term estrogendeprived breast cancer cells (21)(22)(23)(24). The findings that physiological estrogen causes dramatic tumor repression in anti-hormone-resistant breast cancer (17,18) are reminiscent of the early clinical trials utilizing high doses of diethylstilbestrol (DES) (25,26) to treat breast cancer in post-menopausal patients many years after their menopause.…”

Section: Introductionmentioning

confidence: 62%

Raloxifene-stimulated experimental breast cancer with the paradoxical actions of estrogen to promote or prevent tumor growth: A unifying concept in anti-hormone resistance

Jordan¹,

Dardes

Johnson

et al. 2010

Int J Oncol

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Abstract.We have previously demonstrated that prolonged treatments with raloxifene (RAL) in vitro will result in phase II RAL resistance and RAL-induced tumor growth. Clinical interest prompted us to re-examine RAL resistance in vivo, particularly the effects of long-term treatments (a decade or more) on the evolution of RAL resistance. In this study, we have addressed the question of this being a reproducible phenomenon in wild-type estrogen receptor (ER)-positive human breast cell line MCF-7. MCF-7 cells cultured under estrogen-deprived conditions in the presence of 1 μM RAL for more than a year develop RAL resistance resulting in an independent cell line, MCF7-RAL. The MCF7-RAL cells grow in response to both estradiol E 2 and RAL. Fulvestrant (FUL) blocks RAL and E 2 -mediated growth. Transplantation of MCF7-RAL cells into athymic ovariectomized mice and treatment with physiologic doses of E 2 causes early E 2 -stimulated tumor growth. In contrast, continuous treatment of implanted animals with daily oral RAL (1.5 mg daily) causes growth of small tumors within 15 weeks. Continuous re-transplantation of the tumors growing in RAL-treated mice indicated that RAL stimulated tumor growth. Tumors in the untreated mice did not grow. Bi-transplantation of MCF7-E 2 and MCF7-RAL tumors into the opposing mammary fat pads of the same ovariectomized animal demonstrated that MCF7-E 2 grew with E 2 stimulation and not with RAL. Conversely, MCF7-RAL tumors grew with RAL and not E 2 , a characteristic of phase II resistance. Established phase II resistance of MCF7-RAL tumors was confirmed following up to 7 years of serial transplantation in RAL-treated athymic mice. The ER· was retained in these tumors. The cyclical nature of RAL resistance was confirmed and extended during a 2-year evolution of the resistant phases of the MCF7-RAL tumors. The MCF7-RAL tumors that initially were inhibited by E 2 grew in the presence of E 2 and subsequently grew with either RAL or E 2 . RAL remained the major grow stimulus and RAL enhanced E 2 -stimulated growth. Subsequent transplantation of E 2 stimulated tumors and evaluations of the actions of RAL, demonstrated robust E 2 -stimulated growth that was blocked by RAL. These are the characteristics of the antiestrogenic actions of RAL on E 2 -stimulated breast cancer growth with a minor component of phase I RAL resistance. Continuous transplantation of the phase I RAL-stimulated tumors for >8 months causes reversion to phase II resistance. These data and literature reports of the cyclical nature of anti-androgen/androgen responsiveness of prostate cancer growth, illustrate the generality of the evolution of antihormonal resistance in sex steroid-sensitive target tissues.

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Estrogen-induced apoptosis in a breast cancer model resistant to long-term estrogen withdrawal

Cited by 115 publications

References 42 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

Celebrating 75 years of oestradiol

Raloxifene-stimulated experimental breast cancer with the paradoxical actions of estrogen to promote or prevent tumor growth: A unifying concept in anti-hormone resistance

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