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Buwalda B, Schagen SBIs basic research providing answers if adjuvant anti-estrogen treatment of breast cancer can induce cognitive impairment? Life Sci 93: 581-588

Behavioral Physiology, University of Groningen, Nijenborgh 7, 9747 AG Groningen, the Netherlands. Electronic address: .
Life sciences (Impact Factor: 2.3). 01/2013; 93(17). DOI: 10.1016/j.lfs.2012.12.012
Source: PubMed

ABSTRACT Adjuvant treatment of cancer by chemotherapy is associated with cognitive impairment in part of the cancer survivors. Breast cancer patient are frequently also receiving endocrine therapy with selective estrogen receptor modulators (SERM's) and/or aromatase inhibitors (AI's) to suppress the growth of estradiol sensitive breast tumors. Estrogens are well-known, however, to target brain areas involved in the regulation of cognitive behavior. In this review clinical and basic preclinical research is reviewed on the actions of estradiol, SERM's and AI's on brain and cognitive functioning to see if endocrine therapy potentially induces cognitive impairment and in that respect may contribute to the detrimental effects of chemotherapy on cognitive performance in breast cancer patients. Although many clinical studies may be underpowered to detect changes in cognitive function, current basic and clinical reports suggest that there is little evidence that AI's may have a lasting detrimental effect on cognitive performance in breast cancer patients. The clinical data on SERM's are not conclusive, but some studies do suggest that tamoxifen administration may form a risk for cognitive functioning particularly in older women. An explanation may come from basic preclinical research which indicates that tamoxifen often acts agonistic in the absence of estradiol but antagonistic in the presence of endogenous estradiol. It could be hypothesized that the negative effects of tamoxifen in older women is related to the so-called window of opportunity for estrogen. Administration of SERM's beyond this so-called window of opportunity may not be effective or might even have detrimental effects similar to estradiol.

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    • "Initially, researchers studied cognitive changes and found that this phenomenon was associated with chemotherapy treatment (Ahles and Saykin, 2007). However, some studies have recently shown that adjuvant endocrine therapies which play a key role in hormone-sensitive breast cancer treatment are a potential cause of this cognitive dysfunction (Buwalda and Schagen, 2013; Phillips et al., 2011). "
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    ABSTRACT: The selective estrogen receptor modulator tamoxifen (TAM) is most commonly prescribed for patients with hormone-sensitive breast cancer. Although TAM can bind to estrogen receptors in the nervous system, it is unknown whether it acts as an estrogen agonist or antagonist in the human brain. Several studies have reported the negative effects of TAM on cognitive function; however, its effects on decision-making function have not been previously explored. The present study aimed to investigate the decision-making function under ambiguity and risk in breast cancer patients treated with TAM. Participants included breast cancer patients taking TAM (TAM, N = 47) and breast cancer patients not taking TAM (non-TAM, N = 45) as well as their matched healthy controls (HC, N = 50). All participants were given the Iowa Gambling Task (IGT) to assess their decision-making under conditions involving ambiguity, the Game of Dice Task (GDT) to assess their decision-making under conditions involving risk, and a battery of neuropsychological tests. Our results indicated that patients in the TAM group were significantly impaired as assessed by both the IGT and GDT and performed significantly worse on some aspects of various tasks involving memory and information processing. Furthermore, we found that decreased performance on verbal memory testing significantly correlated with IGT performance, and executive dysfunction was associated with poor GDT performance in breast cancer patients undergoing TAM treatment. This study demonstrates that breast cancer patients taking TAM have several decision-making impairments. These findings may support the idea that TAM resulting in cognitive changes plays an antagonistic role in the areas of the brain where estrogen receptors are present, including the prefrontal cortex, hippocampus and amygdala.
    Hormones and Behavior 07/2014; 66(2). DOI:10.1016/j.yhbeh.2014.07.005 · 4.51 Impact Factor
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    • "Tamoxifen is a selective oestrogen receptor modulator (SERM), with tissue specific effects on oestrogen receptors as well as second messenger pathways (Lam, 1984). Tamoxifen has mainly 'anti-estrogenic' effects in many parts of the CNS, although studies are largely inconclusive (Paganini-Hill and Clark, 2000; Buwalda and Schagen, 2013). Several small studies have also demonstrated a clinical benefit of tamoxifen in the treatment of mania (Manji and Lenox, 1999; Bebchuk et al., 2000; Zarate et al., 2007; DiazGranados and Zarate, 2008; Yildiz et al., 2008; Amrollahi et al., 2011; Yildiz et al., 2011). "
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    ABSTRACT: Emerging research has suggested that hormone treatments such as selective estrogen receptor modulators (SERMs) or progestins may be useful in the treatment of mania. The current pilot study compared the use of the SERM tamoxifen and the progestin medroxyprogesterone acetate (MPA), as an adjunct to mood stabiliser medications, for the treatment of mania symptoms in 51 women in a 28-day double blind, placebo controlled study. The primary outcome was the change between baseline and day 28 mania scores as measured by the Clinician Administered Rating Scale for Mania (CARS-M). Adjunctive MPA treatment provided greater and more rapid improvement in mania symptoms compared with adjunctive placebo and tamoxifen treatment. Adjunctive therapy with MPA may be a potentially useful new treatment for persistent mania, leading to a greater and more rapid resolution of symptoms compared with mood stabiliser treatment alone.
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    ABSTRACT: Breast cancer is the leading cause of cancer death for women worldwide. Various therapeutic approaches have been proposed, among which endocrine therapy has recently become popular due to the high sensitivity of breast tissues to steroids such as estrogens and progesterone. The underlying mechanisms of steroid regulation in breast cancer cell proliferation, invasiveness, metastasis and endocrine resistance, however, remain largely unknown. Steroid receptor coactivator-1 (SRC-1) has attracted much attention because it is an important co-regulator and plays a pivotal role in modulating the transcriptional activities of steroid nuclear receptors. Accumulated research has established a strong correlation between SRC-1 and the pathological progression or disease-related features of breast cancer, which supports its potential as a target for specific therapeutic intervention in the clinical management of breast cancer. In addition, a diverse group of downstream molecules have also been shown to participate in various functional pathways related to SRC-1-associated regulation of breast cancer. These downstream molecules are also considered promising therapeutic targets, providing additional options for targeted treatments. In this review, the expression of SRC-1 in breast cancer and the close relationships between SRC-1 and the cell proliferation, invasiveness, metastasis and endocrine resistance of breast cancer will be discussed, followed by a brief summary of its putative functional mechanisms with an emphasis on the potential therapeutic role of SRC-1.
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