Mechanisms underlying differential response to estrogen-induced apoptosis in long-term estrogen-deprived breast cancer cells

Sweeney, Elizabeth E.; Fan, Ping; Jordan, V. Craig

doi:10.3892/ijo.2014.2329

Cited by 30 publications

(76 citation statements)

References 17 publications

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“…Using buthionine sulphoximine (BSO)(113, 114), that inhibits glutathione biosynthesis, estrogen induced apoptosis was advanced to occur during the first six days of estrogen-treatment. Recent studies have built on these original findings (115). …”

Section: The Few Er Positive Breast Cancer Cell Linesmentioning

confidence: 99%

The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer

Jordan¹

2014

Endocrine-Related Cancer

121

100

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The successful use of high dose synthetic estrogens to treat post-menopausal metastatic breast cancer, is the first effective “chemical therapy” proven in clinical trial to treat any cancer. This review documents the clinical use of estrogen for breast cancer treatment or estrogen replacement therapy (ERT) for postmenopausal hysterectomized women which can either result in breast cancer cell growth or breast cancer regression. This has remained a paradox since the 1950s until the discovery of the new biology of estrogen induced apoptosis at the end of the 20th century. The key to triggering apoptosis with estrogen is the selection of breast cancer cell populations that are resistant to long term estrogen deprivation. However, through trial and error estrogen independent growth occurs. At the cellular level, estrogen induced apoptosis is dependent upon the presence of the estrogen receptor (ER) which can be blocked by non-steroidal or steroidal anti-estrogens. The shape of an estrogenic ligand programs the conformation of the ER complex which in turn can modulate estrogen induced apoptosis: class I planar estrogens (eg: estradiol) trigger apoptosis after 24 hours whereas class II angular estrogens (eg: bisphenol triphenylethylene) delay the process until after 72 hours. This contrasts with paclitaxel that causes G2 blockade with immediate apoptosis. The process is complete within 24 hours. Estrogen induced apoptosis is modulated by glucocorticoids and cSrc inhibitors but the target mechanism for estrogen action is genomic and not through a non-genomic pathway. The process is step wise through the creation of endoplasmic reticulum stress and, inflammatory responses that then initiate an unfolded protein response. This in turn initiates apoptosis through the intrinsic pathway (mitochondrial) with subsequent recruitment of the extrinsic pathway (death receptor) to complete the process. The symmetry of the clinical and laboratory studies now permits the creation of rules for the future clinical application of ERT or phytoestrogen supplements: a five year gap is necessary after menopause to permit the selection of estrogen deprived breast cancer cell populations to become vulnerable to apoptotic cell death. Earlier treatment with estrogen around the menopause encourages ER positive tumor cell growth, as the cells are still dependent on estrogen to maintain replication within the expanding population. An awareness of the evidence that the molecular events associated with estrogen induced apoptosis can be orchestrated in the laboratory in estrogen deprived breast cancers, now support the clinical findings for the treatment of metastatic breast cancer following estrogen deprivation, decreases in mortality following long term antihormonal adjuvant therapy, and the results of ERT and ERT plus progestin in the Women’s Health Initiative for women over the age of 60. Principles have emerged to understand and apply physiologic estrogen therapy appropriately by targeting the correct patient populations.

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Section: The Few Er Positive Breast Cancer Cell Linesmentioning

confidence: 99%

The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer

Jordan¹

2014

Endocrine-Related Cancer

121

100

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“…Our previous findings show that c-Src activity is increased in two long-term E 2 -deprived breast cancer cells (11), which mediates the non-genomic and genomic pathways of E 2 (12). In addition to the role of c-Src in growth, the oncogene participates in stress responses induced by E 2 (12), which are critical to induce apoptosis (12-14). Inhibition of c-Src blocks E 2 -induced apoptosis (12,15).…”

Section: Introductionmentioning

confidence: 99%

Identification of gene regulation patterns underlying both oestrogen- and tamoxifen-stimulated cell growth through global gene expression profiling in breast cancer cells

Fan

Cunliffe

Agboke

et al. 2014

European Journal of Cancer

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Purpose A c-Src inhibitor blocks estrogen (E2)-induced stress and converts E2 responses from inducing apoptosis to growth stimulation in E2-deprived breast cancer cells. A reprogrammed cell line, MCF-7:PF, results in a functional estrogen receptor (ER). We addressed the question of whether the selective ER modulator 4-hydroxytamoxifen (4-OHT) could target ER to prevent E2-stimulated growth in MCF-7:PF cells. Methods Expression of mRNA was measured through real-time RT-PCR. Global gene expression profile was analyzed through microarray. Transcriptome profiles were screened by RNA-sequencing. Results Unexpectedly, both 4-OHT and E2 stimulated cell growth in a concentration-dependent manner. Expression profiling showed a remarkable overlap in genes regulated in the same direction by E2 and 4-OHT. Pathway enrichment analysis of the 280 genes commonly deregulated in MCF-7:PF cells by 4-OHT and E2 revealed functions mainly related to membrane, cytoplasm, and metabolic processes. Further analysis of 98 genes up-regulated by both 4-OHT and E2 uncovered a significant enrichment in genes associated with membrane remodeling, cytoskeleton reorganization, cytoplasmic adapter proteins, cytoplasm organelles proteins, and related processes. 4-OHT was more potent than E2 in up-regulating some membrane remodeling molecules, such as EHD2, FHL2, HOMER3 and RHOF. In contrast, 4-OHT acted as an antagonist to inhibit expression of the majority of enriched membrane-associated genes in wild-type MCF-7 cells. Conclusions Long-term selection pressure has changed the cell population responses to 4-OHT. Membrane-associated signaling is critical for 4-OHT-stimulated cell growth in MCF-7:PF cells. This study provides a rationale for the further investigation of target therapy for tamoxifen resistant patients.

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“…Our recent publications establish that estrogen induces apoptosis through endoplasmic reticulum stress and oxidative stress (84, 87, 94). A variety of apoptosis-related genes are activated by estrogen in MCF-7:5C and MCF-7:2A cells (84, 94, and Fig.…”

Section: Drug Resistance To Sermsmentioning

confidence: 97%

“…The MCF-7:2A cells had a delayed apoptotic response based on increased glutathione levels; slow cell death could be triggered by physiological estrogen after 7 days and enhanced apoptosis facilitated using the blocker of glutathione synthesis, buthionine sulfoximine (BSO) (82–84). Changing media conditions caused early catastrophic apoptosis with physiological estrogen in MCF-7:5C cells within a week (85, 86).…”

Section: Drug Resistance To Sermsmentioning

confidence: 99%

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Acquired resistance to selective estrogen receptor modulators (SERMs) in clinical practice (tamoxifen & raloxifene) by selection pressure in breast cancer cell populations

Fan

Jordan

2014

Steroids

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Tamoxifen, a pioneering selective estrogen receptor modulator (SERM), has long been a therapeutic choice for all stages of estrogen receptor (ER)-positive breast cancer. The clinical application of long-term adjuvant antihormone therapy for the breast cancer has significantly improved breast cancer survival. However, acquired resistance to SERM remains a significant challenge in breast cancer treatment. The evolution of acquired resistance to SERMs treatment was primarily discovered using MCF-7 tumors transplanted in athymic mice to mimic years of adjuvant treatment in patients. Acquired resistance to tamoxifen is unique because the growth of resistant tumors is dependent on SERMs. It appears that acquired resistance to SERM is initially able to utilize either E2 or a SERM as the growth stimulus in the SERM-resistant breast tumors. Mechanistic studies reveal that SERMs continuously suppress nuclear ER-target genes even during resistance, whereas they function as agonists to activate multiple membrane-associated molecules to promote cell growth. Laboratory observations in vivo further show that three phases of acquired SERM-resistance exists, depending on the length of SERMs exposure. Tumors with Phase I resistance are stimulated by both SERMs and estrogen. Tumors with Phase II resistance are stimulated by SERMs, but are inhibited by estrogen due to apoptosis. The laboratory models suggest a new treatment strategy, in which limited-duration, low-dose estrogen can be used to purge Phase II-resistant breast cancer cells. This discovery provides an invaluable insight into the evolution of drug resistance to SERMs, and this knowledge is now being used to justify clinical trials of estrogen therapy following long-term antihormone therapy. All of these results suggest that cell populations that have acquired resistance are in constant evolution depending upon selection pressure. The limited availability of growth stimuli in any new environment enhances population plasticity in the trial and error search for survival.

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Mechanisms underlying differential response to estrogen-induced apoptosis in long-term estrogen-deprived breast cancer cells

Cited by 30 publications

References 17 publications

The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer

The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer

Identification of gene regulation patterns underlying both oestrogen- and tamoxifen-stimulated cell growth through global gene expression profiling in breast cancer cells

Acquired resistance to selective estrogen receptor modulators (SERMs) in clinical practice (tamoxifen & raloxifene) by selection pressure in breast cancer cell populations

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