Estrogen as therapy for breast cancer

Ingle, James N.

doi:10.1186/bcr436

Cited by 56 publications

(39 citation statements)

References 19 publications

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“…The interdependence of HIF and ERR suggests that inhibition of ERRs may be a tractable approach to abrogating hypoxiainduced gene expression and malignant progression. The ERR inhibitor DES has exhibited clinically proven antitumor efficacy for advanced breast cancer, although the mechanisms underlying cancer regression are poorly understood (15). Breast cancer often progresses from an early ER-positive stage to an advanced ER-negative stage.…”

Section: Discussionmentioning

confidence: 99%

“…Tamoxifen became preferable to DES not because of a superior efficacy but rather because of its lower incidence of side effects. The efficacy of the ER antagonist tamoxifen and the ER agonist DES was surprisingly comparable (15,16). Survival was even modestly but significantly better for women treated with DES (16).…”

Section: Tional Activation Of Hypoxic Genes In Cells Cultured Under Hmentioning

confidence: 96%

“…Antiestrogen administration [e.g., the estrogen receptor (ER) antagonist tamoxifen] is applied on the rationale that estrogens stimulate proliferation of breast cancer cells. Paradoxically, the synthetic estrogen diethylstilbestrol (DES) was used clinically to achieve cancer remission (15). High-dose DES was generally considered the endocrine therapy of choice in women with advanced breast cancer before the introduction of tamoxifen in the 1970s.…”

Section: Tional Activation Of Hypoxic Genes In Cells Cultured Under Hmentioning

confidence: 99%

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Involvement of estrogen-related receptors in transcriptional response to hypoxia and growth of solid tumors

Wang

Kamarajugadda

et al. 2008

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

117

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The development of intratumoral hypoxia is a universal hallmark of rapidly growing solid tumors. Adaptation to the hypoxic environment, which is critical for tumor cell survival and growth, is mediated primarily through a hypoxia-inducible factor (HIF)-dependent transcriptional program. HIF activates genes that facilitate crucial adaptive mechanisms including increased glucose uptake and glycolysis and tumor angiogenesis, making it an important therapeutic target. However, the HIF-dependent transcriptional mechanism remains incompletely understood, and targeting HIF is a difficult endeavor. Here, we show that the orphan nuclear receptor estrogen-related receptors (ERRs) physically interact with HIF and stimulate HIF-induced transcription. Importantly, ERRs appear to be essential for HIF's function. Transcriptional activation of hypoxic genes in cells cultured under hypoxia is largely blocked by suppression of ERRs through expression of a dominant negative form of ERR or treatment with a pharmacological ERR inhibitor, diethylstilbestrol. Systematic administration of diethylstilbestrol severely diminished growth and angiogenesis of tumor xenografts in vivo. Because nuclear receptors are outstanding targets for drug discovery, the findings not only may offer mechanistic insights into HIF-mediated transcription but also may open new avenues for targeting the HIF pathway for cancer therapy.angiogenesis ͉ energy metabolism ͉ nuclear hormone receptor R apidly growing solid tumors tend to outstrip the supply of oxygen and nutrients provided by blood vessels, resulting in regions of low oxygen levels (hypoxia). Cancer cells undergo adaptation to persist in the hostile hypoxic environment. The adaptive response to hypoxia is controlled primarily by the hypoxia-inducible factor (HIF), a master regulator of hypoxic gene expression and oxygen homeostasis (1-3). HIF is a heterodimeric transcription factor comprising an oxygen-regulated ␣-subunit (HIF1␣ or -2␣) and a constitutively expressed and stable ␤-subunit (HIF␤). Under normal oxygen tension, the HIF␣ subunit is subjected to prolyl hydroxylation catalyzed by a set of oxygen-and ferrous ion-dependent prolyl hydroxylases. Hydroxylated HIF␣ is recognized by the tumor-suppressor protein von Hippel-Lindau (VHL), a component of an E3 ubiquitin ligase complex. Subsequently, HIF␣ becomes polyubiquitinated and is targeted for rapid degradation by the proteasomal system. Oxygen deprivation, or administration of iron chelators or cobaltous ion (a classic hypoxia mimetic, which competes with ferrous ion), suppresses hydroxylase activity, allowing HIF␣ to escape the VHL-mediated destruction and to accumulate and dimerize with the constitutively present HIF␤. The binding of the HIF␣-HIF␤ heterodimer along with the transcriptional coactivator p300/CBP to the cognate hypoxia-responsive element (HRE) augments the expression of a plethora of hypoxic genes that carry such elements within their promoters or enhancers (4). The HIF-orchestrated transcriptional program is directly responsible ...

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Section: Discussionmentioning

confidence: 99%

Section: Tional Activation Of Hypoxic Genes In Cells Cultured Under Hmentioning

confidence: 96%

Section: Tional Activation Of Hypoxic Genes In Cells Cultured Under Hmentioning

confidence: 99%

See 1 more Smart Citation

Involvement of estrogen-related receptors in transcriptional response to hypoxia and growth of solid tumors

Wang

Kamarajugadda

et al. 2008

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

117

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“…The data available on these strategies are limited, but the response rates are generally less than 10%. In fact, perhaps the most active approach may be pharmacological doses of oestrogen (Ingle, 2002), which would concur with the apoptotic response of long-term oestrogen deprived cells to the reintroduction of oestrogen (Song et al, 2001).…”

Section: Interpretation Of the Advanced Disease Datamentioning

confidence: 99%

First-line endocrine treatment of breast cancer: aromatase inhibitor or antioestrogen?

Ellis

2004

Br J Cancer

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Until recently, endocrine therapy for breast cancer was relatively simple. If the tumour expressed hormone receptors, regardless of stage and age, tamoxifen was indicated. While this largely remains the case for premenopausal women, clinical trials in postmenopausal women have broadened our choice to include one of three selective aromatase inhibitors (AIs), the nonsteroidal agents anastrozole or letrozole and the steroidal agent exemestane. Comparative data concerning the efficacy, toxicity, tolerability and cost of AI vs tamoxifen continues to evolve with over 40 000 women slated to be involved in clinical trials. Currently, tamoxifen remains an appropriate choice for adjuvant treatment, and will remain so unless a clear survival advantage emerges for adjuvant AI therapy. However, anastrozole is widely seen as a useful alternative, with particular merit for patients prone to the development of serious tamoxifen side effects. For endocrine therapy naïve advanced disease, several trials have provided evidence that a nonsteroidal AI has replaced tamoxifen as optimal treatment. In the neoadjuvant setting, letrozole was also more effective than tamoxifen, both in terms of response rates and the incidence of breast-conserving surgery, and so AI therefore also dominates this evolving indication. The ongoing adjuvant clinical trials ask all the relevant questions regarding tamoxifen and AI in combination, sequence and duration, except for 5 years of an AI vs a longer period. For both the advanced and early-stage disease, resistance remains the key obstacle to overcome, and trials that combine endocrine agents with signal transduction inhibitors such as HER1 and HER2 kinase inhibitors, farnesyl transferase inhibitors, mTOR inhibitors as well as COX2 inhibitors are being developed in a concerted attempt to address this problem.

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“…However, clinical clues are emerging that the practice of exhaustive antihormonal therapy is not always appropriate, and useful palliation can occur with an application of the obsolete modality of pharmacological oestrogen treatment (diethylstilboestrol, 5 mg three times a day). Renewed interest in re-treating endocrine refractory disease with highdose oestrogen has demonstrated improvement in the anecdotal patient (Ingle, 2002) and remarkable responses in metastatic breast cancer patients treated exhaustively with antihormonal therapies (Lonning et al, 2001). Out of 32 evaluable patients, four had complete response, six had partial response and two had stable disease.…”

Section: Clinical Correlationsmentioning

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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Estrogen as therapy for breast cancer

Cited by 56 publications

References 19 publications

Involvement of estrogen-related receptors in transcriptional response to hypoxia and growth of solid tumors

Involvement of estrogen-related receptors in transcriptional response to hypoxia and growth of solid tumors

First-line endocrine treatment of breast cancer: aromatase inhibitor or antioestrogen?

Targeting oestrogen to kill the cancer but not the patient

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