Cross-resistance to different aromatase inhibitors in breast cancer treatment.

Lønning, PE

doi:10.1677/erc.0.0060251

Cited by 15 publications

(4 citation statements)

References 37 publications

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“…Although longer follow-up may be required to fully assess the long-term effects of anastrozole on bone mineral density and overall survival, this agent has been recently recommended for adjuvant use in postmenopausal women with early, ER-positive breast cancer [43]. Even though resistance to AIs may develop, sequencing non-steroidal and steroidal agents may be an option [44].…”

Section: Aromatase Inhibitorsmentioning

confidence: 99%

Endocrine therapy – current benefits and limitations

Nicholson

Johnston

2005

Breast Cancer Res Treat

118

107

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Endocrine therapy is a valuable option for the treatment of postmenopausal women with estrogen receptor (ER)-positive breast cancer due to its demonstrated efficacy and favorable safety profile. Although tamoxifen has been the established treatment for more than 20 years its long-term use is associated with several tolerability concerns and may lead to increased risk of endometrial cancer and thromboembolic complications. In addition, many patients who initially respond to treatment with endocrine agents such as tamoxifen eventually relapse with resistant disease. Sequential use of endocrine therapies is often used in patients as resistance to individual agents develops. Several endocrine approaches have been developed that deprive the tumor of estrogen stimulation, either by directly modulating the ER-signaling pathway or by lowering serum or tumor concentrations of estrogen. In the classic pathway of estrogen signal transduction, the steroid hormone binds to its intracellular ER, triggering a cascade of events that ultimately leads to altered gene transcription. More recently, it has become apparent that ER activation can also occur via estrogen-independent receptor activation or by non-nuclear action through cell surface receptors. Consequently, molecular cross-talk exists between the ER and growth factor signaling cascades, which is a key factor in de novo and acquired resistance to endocrine therapy. Inappropriate activation of growth factor signaling can readily promote endocrine therapy failure in breast cancer cells, either by overriding the growth-inhibitory properties of antiestrogenic drugs or by establishment of a new self-propagating autocrine loop that efficiently drives resistant cell growth. Fulvestrant is a new type of ER antagonist with no agonist effects that binds, blocks and causes degradation of the ER. As multiple signaling pathways are involved in the activation of ER, the use of agents such as fulvestrant that directly target the ER and lead to both degradation of the receptor and abrogation of ER signaling may prevent or delay the development of absolute endocrine resistance. In addition, combining antiestrogenic drugs with inhibitors of cell signaling molecules to target both the ER and growth factor signaling pathways is likely to provide a means of delaying endocrine therapy resistance, leading the way to more effective breast cancer treatment.

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Section: Aromatase Inhibitorsmentioning

confidence: 99%

Endocrine therapy – current benefits and limitations

Nicholson

Johnston

2005

Breast Cancer Res Treat

118

107

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“…Progression to disease following use of non-steroidal AIs has lead physicians to switch non-steroidal AIs to steroidal AI while achieving clinical benefit [128]. Lack of AI cross-resistance cannot be explained by drug efficacy as all AIs inhibit total body aromatase to a similar degree; however, the exact mechanism(s) responsible are not fully elucidated [129–131]. …”

Section: Aromatasementioning

confidence: 99%

Structural and functional characterization of aromatase, estrogen receptor, and their genes in endocrine-responsive and –resistant breast cancer cells

Chan

Petrossian

Chen

2016

The Journal of Steroid Biochemistry and Molecular Biology

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Aromatase and estrogen receptor α (ER) are two key proteins for the proliferation of endocrine-responsive and – resistant breast cancers. Aromatase is an enzyme involved in the conversion of androgen (such as testosterone) to estrogen (such as 17β-estradiol). It is also a very effective therapeutic target for the treatment of endocrine-responsive breast cancer. Comparing endocrine-responsive and -resistant breast cancer, aromatase protein levels do not change significantly. Aromatase activity; however, can be increased via PI3K/Akt/IGFR signaling pathways in endocrine resistant cells. The activity of aromatase has been reported to be modulated by phosphorylation. The ER is an important steroid nuclear receptor in the proliferation of both endocrine-responsive and -resistant cells. Although the mutation or amplification of ER can cause endocrine resistance, it is not commonly found. Some point mutations and translocation events have been characterized and shown to promote estrogen-independent growth. Phosphorylation by cross-talk with growth factor pathways is one of the main mechanisms for ligand-independent activation of ER. Taken together, both ER and aromatase are important in ER-dependent breast cancer and the development of endocrine resistance.

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“…This issue has been [20] reviewed extensively in the last years [69][70][71][72][73] and it would be beyond the scope of this article to give a comprehensive overview about resistance to aromatase inhibition. Thus, only some of the major topics will be mentioned briefly.…”

Section: Resistance To Aromatase Inhibitionmentioning

confidence: 99%

Aromatase inhibitors: from bench to bedside and back

Geisler

2007

Breast Cancer

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The development of the novel "third generation" aromatase inhibitors (anastrozole, letrozole) and inactivators (exemestane) is one of the most successful contemporary achievements in breast cancer therapy. While clinical studies evaluated toxicity and efficacy in metastatic disease, the endocrine effects of multiple compounds were evaluated in parallel, identifying the most potent aromatase inhibitors based on estrogen deprivation in plasma and tissue samples in addition to "total body aromatase inhibition" in vivo. Thus, "translational" studies have been of vital importance identifying the unique characteristics of these drugs. While first- and second generation aromatase inhibitors inhibit estrogen synthesis in vivo by up to 90%, third generation compounds like anastrozole, exemestane and letrozole were shown to cause > or = 98% aromatase inhibition in humans. The present paper summarises and discusses the "translational research" that provided the background for the implementation of the third generation aromatase inhibitors and inactivators into large clinical trials and later on in clinical use. Finally, some of the major topics of currently ongoing translational research programs are presented. These programs focus on aromatase regulation in different tissues, mechanisms of resistance to aromatase inhibition and strategies to overcome resistance like combined therapy with aromatase inhibitors and intracellular signal transduction inhibitors.

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Cross-resistance to different aromatase inhibitors in breast cancer treatment.

Cited by 15 publications

References 37 publications

Endocrine therapy – current benefits and limitations

Endocrine therapy – current benefits and limitations

Structural and functional characterization of aromatase, estrogen receptor, and their genes in endocrine-responsive and –resistant breast cancer cells

Aromatase inhibitors: from bench to bedside and back

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