Targeted therapy—anastrozole prevents breast cancer

Brown, Powel H.

doi:10.1038/nrclinonc.2014.17

Cited by 8 publications

(8 citation statements)

References 10 publications

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“…Consequently, it is important to identify effective breast cancer preventive strategies in high-risk women who need to take these types of antipsychotics. There are currently only a few US Food and Drug Administrtion (FDA)-approved drugs for breast cancer chemoprevention, all of which antagonize estrogen signaling [ 62 ]. As these drugs require 5 years of continuous treatment to lower breast cancer risk by 50%, do not prevent estrogen receptor (ER)-negative cancer, and can have significant side effects, they are not widely used for prevention [ 62 ].…”

Section: Resultsmentioning

confidence: 99%

Hyperprolactinemia-inducing antipsychotics increase breast cancer risk by activating JAK-STAT5 in precancerous lesions

Johnston

Hein

et al. 2018

Breast Cancer Res

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BackgroundPsychiatric medications are widely prescribed in the USA. Many antipsychotics cause serum hyperprolactinemia as an adverse side effect; prolactin-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling both induces cell differentiation and suppresses apoptosis. It is controversial whether these antipsychotics increase breast cancer risk.MethodsWe investigated the impact of several antipsychotics on mammary tumorigenesis initiated by retrovirus-mediated delivery of either ErbB2 or HRas or by transgenic expression of Wnt-1.ResultsWe found that the two hyperprolactinemia-inducing antipsychotics, risperidone and pimozide, prompted precancerous lesions to progress to cancer while aripiprazole, which did not cause hyperprolactinemia, did not. We observed that risperidone and pimozide (but not aripiprazole) caused precancerous cells to activate STAT5 and suppress apoptosis while exerting no impact on proliferation. Importantly, we demonstrated that these effects of antipsychotics on early lesions required the STAT5 gene function. Furthermore, we showed that only two-week treatment of mice with ruxolitinib, a JAK1/2 inhibitor, blocked STAT5 activation, restored apoptosis, and prevented early lesion progression.ConclusionsHyperprolactinemia-inducing antipsychotics instigate precancerous cells to progress to cancer via JAK/STAT5 to suppress the apoptosis anticancer barrier, and these cancer-promoting effects can be prevented by prophylactic anti-JAK/STAT5 treatment. This preclinical work exposes a potential breast cancer risk from hyperprolactinemia-inducing antipsychotics in certain patients and suggests a chemoprevention regime that is relatively easy to implement compared to the standard 5-year anti-estrogenic treatment in women who have or likely have already developed precancerous lesions while also requiring hyperprolactinemia-inducing antipsychotics.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-0969-z) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Hyperprolactinemia-inducing antipsychotics increase breast cancer risk by activating JAK-STAT5 in precancerous lesions

Johnston

Hein

et al. 2018

Breast Cancer Res

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“…However, breastfeeding can and should be encouraged for many reasons, including possibly for the reduction of breast cancer risk. Many of the risks of reproductive factors are related to the effects of estrogen as demonstrated by the reduction in breast cancer incidence after an early oophorectomy, by inhibition of the estrogen receptor (ER) by using selective estrogen receptor modulators (SERMs) such as a tamoxifen or raloxifene [ 9 ], or by blocking estrogen synthesis by using aromatase inhibitors (AIs) such as exemestane [ 10 ] and anastrozole [ 11 ],[ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Risk determination and prevention of breast cancer

et al. 2014

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Breast cancer is an increasing public health problem. Substantial advances have been made in the treatment of breast cancer, but the introduction of methods to predict women at elevated risk and prevent the disease has been less successful. Here, we summarize recent data on newer approaches to risk prediction, available approaches to prevention, how new approaches may be made, and the difficult problem of using what we already know to prevent breast cancer in populations. During 2012, the Breast Cancer Campaign facilitated a series of workshops, each covering a specialty area of breast cancer to identify gaps in our knowledge. The risk-and-prevention panel involved in this exercise was asked to expand and update its report and review recent relevant peer-reviewed literature. The enlarged position paper presented here highlights the key gaps in risk-and-prevention research that were identified, together with recommendations for action. The panel estimated from the relevant literature that potentially 50% of breast cancer could be prevented in the subgroup of women at high and moderate risk of breast cancer by using current chemoprevention (tamoxifen, raloxifene, exemestane, and anastrozole) and that, in all women, lifestyle measures, including weight control, exercise, and moderating alcohol intake, could reduce breast cancer risk by about 30%. Risk may be estimated by standard models potentially with the addition of, for example, mammographic density and appropriate single-nucleotide polymorphisms. This review expands on four areas: (a) the prediction of breast cancer risk, (b) the evidence for the effectiveness of preventive therapy and lifestyle approaches to prevention, (c) how understanding the biology of the breast may lead to new targets for prevention, and (d) a summary of published guidelines for preventive approaches and measures required for their implementation. We hope that efforts to fill these and other gaps will lead to considerable advances in our efforts to predict risk and prevent breast cancer over the next 10 years.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0446-2) contains supplementary material, which is available to authorized users.

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“…[2] Indeed potent and selective inhibitors of targeted CYPs have been extensively pursued and many efficient drugs discovered. Aromatase (CYP 19) [3][4][5] and 17β-hydroxylase/17,20-lyase (CYP17) [6] inhibitors are well known examples of CYPs inhibitors largely used in breast and prostate cancer, respectively (Chart 1). More recently, two additional CYP enzymes, namely, steroid 11β-hydroxylase (CYP11B1) [7][8][9][10] and aldosterone synthase (CYP11B2), [11][12][13] both involved in the biosynthesis of corticosteroid hormones, have been exploited as possible druggable targets.…”

Section: Introductionmentioning

confidence: 99%

Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4′-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase

Stefanachi

Hanke

Pisani

et al. 2015

European Journal of Medicinal Chemistry

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ABSTRACT:Diseases triggered by an abnormally high level of cortisol (hypercortisolism), such as the Cushing's and metabolic syndromes, could be successfully tackled by inhibitors of CYP11B1, a steroidal cytochrome P450 enzyme that catalyzes the last hydroxylation step of the cortisol biosynthesis. Structural optimization of 7-(benzyloxy)-4-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one 2, a selective aromatase inhibitor, afforded the 4-(1H-imidazol-1-ylmethyl)-7-{[3-(trifluoromethoxy)benzyl]oxy}-2H-chromen-2-one 7, with improved inhibitory potency at human CYP11B1 (IC 50 = 5nM) and an enhanced selectivity over human CYP11B2 (SIB = 25) compared to lead compound 2 (IC 50 = 72nM, SIB=4.0) and metyrapone (IC 50 = 15 nM, SIB= 4.8), a non-selective drug used in the therapy of the Cushing's syndrome. Structure-activity relationship studies allowed the design and optimization of a novel series of potent and selective compounds, that can be regarded as open analogues of 2H-chromen-2-one derivatives.Compound 23, 2-(1H-imidazol-1-yl)-1-(4-{[3(trifluoromethoxy)benzyl]oxy}phenyl) ethanone, was the most interesting inhibitor of the series displaying a high potency at CYP11B1 (IC 50 = 15 nM), increased selectivities over CYP11B2 (SIB= 33), CYP19 (SIB= 390) and CYP17 ( 5% inhibition at 2.5µM concentration).

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Targeted therapy—anastrozole prevents breast cancer

Cited by 8 publications

References 10 publications

Hyperprolactinemia-inducing antipsychotics increase breast cancer risk by activating JAK-STAT5 in precancerous lesions

Hyperprolactinemia-inducing antipsychotics increase breast cancer risk by activating JAK-STAT5 in precancerous lesions

Risk determination and prevention of breast cancer

Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4′-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase

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