抗黄体酮联合Aromatase抑制剂或iNOS终止恒河猴妊娠

[目的]评价抗黄体酮(mifepristone)联合Aromatase抑制剂(letrozole或aminoglutethimide)或iNOS抑制剂(aminoguandine)是否能有效终止恒河猴早期妊娠。[方法]将30只猴子随机分为5组(治疗组每组6只,对照组6只),并在妊娠30,31和32天进行如下处理:对照组,每只动物1ml安慰剂;A组,Mifepristone(1mg/kg,sc.);B组,Mifepristone(sc.)+Letrozole(2.5mg/只sc.);C组,Mifepristone(1mg/kg,sc.)+aminoglute-chimide(50mg/kgsc.,bid);D组,Mifepristone(1mg/kg,sc.)+aminoguanidine(150mg/kg,sc.,bid)。所有妊娠猴在妊娠29天通过超声波确认。[结果]在B、C、D组,所有的动物的妊娠都在妊娠早期被终止(6/6)。A组和对照组的妊娠终止率分别为3/6和2/6。同时,联合用药能够有效排空子宫腔和减少出血。[结论]该处理能有效地终止恒河猴早期妊娠。联合用药比用于女人的妊娠治疗更有效,并减少了流血时间,或许可以代替目前的终止妊娠的医疗方法。

Age-related decrease in aromatase and estrogen receptor （ERα and ERβ） expression in rat testes： protective effect of low caloric diets

Aim： To examine the effects on rat aging of caloric restriction （CR1） and undernutrition （CR2） on the body and on testicular weights, on two enzymatic antioxidants （superoxide dismutase and catalase）, on lipid peroxidation and on the expression of testicular aromatase and estrogen receptors （ER）. Methods： CR was initiated in 1-month-old rats and carried on until the age of 18 months. Results： In control and CR2 rats an age-related decrease of the aromatase and of ER （α and β） gene expression was observed; in parallel a diminution of testicular weights, and of the total number and motility of epididymal spermatozo was recorded. In addition, aging in control and CR2 rats was accompartied by a significant decrease in testicular superoxide dismutase, catalase activities, and an increase in lipid peroxidation level （thiobarbituric acid reactive substance）, associated with alterations of spermatogenesis. Conversely, caloric restriction-treatment exerted a protective effect and all the parameters were less affected by aging. Conclusion： These results indicate that during aging, a low caloric diet （not undernutrition） is beneficial for spermatogenesis and likely improves the protection of the cells via an increase of the cellular antioxidant defense system in which aromatase/ ER could play a role. （Asian J Andro12008 Mar; 10： 177-187）

Concurrent use of aromatase inhibitors and hypofractionated radiation therapy

AIM: To retrospectively assess the acute and long-term toxicity using aromatase inhibitors (AI) therapy concurrently with hypofractionated radiotherapy (HFRT) in breast cancer patients. METHODS: From November 1999 to October 2007, 66 patients were treated with breast HFRT and concurrent AI. In 63 patients (95.5%), HFRT delivered a total dose of 32.5 Gy to the whole breast within 5 wk (five fractions, one fraction per week). Other fractionations were chosen in three patients for the patients' personal convenience. A subsequent boost to the tumor bed was delivered in 35 patients (53.0%). Acute toxicities were scored according to the Common Toxicity Criteria for Adverse Events v3. Late toxicity was defined as any toxicity occurring more than 6 mo after completion of HFRT and was scored according to the Late Effects Normal Tissue Task Force-Subjective, Objective, Management and Analytic scale. RESULTS: At the end of the HFRT course, 19 patients (28.8%) had no irradiation-related toxicity. Acute grade 1-2 epithelitis was observed in 46 patients (69.7%). One grade 3 toxicity (1.5%) was observed. With a median follow-up of 34 mo (range: 12-94 mo), 31 patients (47%) had no toxicity, and 35 patients (53%) presented with grade 1-2 fibrosis. No grade 3 or greater delayed toxicity was observed. CONCLUSION: We found that AI was well tolerated when given concurrently with HFRT. All toxicities were mild to moderate, and no treatment disruption was necessary. Further prospective assessment is warranted.

Shu-Gan-Liang-Xue Decoction Simultaneously Down-regulates Expressions of Aromatase and Steroid Sulfatase in Estrogen Receptor Positive Breast Cancer Cells

Objective：Estradiol （E2） plays an important role in the development of breast cancer.In postmenopausal women,the estrogen can be synthesized via aromatase （CYP19） pathway and steroid-sulfatase （STS） pathway in peripheral tissues,when the production in ovary has ceased.The objective of our study was to explore the effects of Shu-Gan-Liang-Xue Decoction （SGLXD） on the expressions of CYP19 and STS in estrogen receptor positive breast cancer MCF-7 and T47D cells.Methods：The effects of SGLXD on the cell viability of MCF-7 and T47D were analyzed by MTT assay.By quantitative real-time RT-PCR and Western blot,we evaluated the mRNA and protein expressions of CYP19 and STS in MCF-7 and T47D cells after SGLXD treatment.Results：By MTT assay,the cell viability rates of MCF-7 and T47D were significantly inhibited by SGLXD in a dose-dependent manner,the IC50 values were 40.07 mg/ml for MCF-7 cells and 25.62 mg/ml for T47D cells,respectively.As evidenced by real-time PCR and Western blot,the high concentrations of SGLXD significantly down-regulated the expressions of CYP19 and STS both in the transcript level and the protein level.Conclusion：The results suggest that SGLXD is a potential dual aromatase-sulfatase inhibitor by simultaneously down-regulating the expressions of CYP19 and STS in MCF-7 and T47D cells.

Molecular Docking Studies of Estrone-Coumarin Derivatives as Aromatase and 17β-HSD1 Inhibitors Related to Hormone Receptor Positive (HR+) Breast Cancer

Hormone Receptor positive (HR+) breast cancer is the most common malignancy in women. New strategies in the treatments have targeted the estrogen biosynthesis pathways including the inhibition of the aromatase and 17β-HSD1 enzymes. The present work, describes the study of a new family of 9 hybrid compounds derived from estrone attached to a coumarin fragment, linked through different lengths of hydrocarbon chains. The activity of these compounds was evaluated by molecular docking with two relevant enzymes in breast cancer (HR+). It has been proposed nine compounds as 17β-HSD1 inhibitors and six as aromatase inhibitors. We found important interactions with key amino acids at the orthosteric site of each enzyme and their score values compared to the crystallographic ligand. The in silico analysis showed good score values in the proposed compounds, where the steroidal portion presented important interactions with Met374 and Tyr155 in aromatase and in 17β-HSD1 respectively. Highlighting Compounds 2, 5 and 8 with an aromatic ring at the C4 position of the coumarin moiety, which favored arene-H type interactions essential for protein-ligand recognition. In addition, the results related to the 17β-HSD1 enzyme demonstrated how the length of the linker influences the interaction;the best score was found for derivative 8 with a chain of 8 methylenes.

Altered Expression of Aromatase, Estrogen Receptors and Progesterone Receptors in Human Leydig Cell Hyperplasia

Testicular function is regulated by pituitary hormones and also by paracrine and autocrine factors. A number of reports have pointed out the importance of estrogens and progesterone in male reproductive tract. Recently, we have reported in testicular biopsies from men with Sertoli Cell Only Syndrome (SCO) or Hypospermatogenesis (H) with Leydig cell hyperplasia (LCH) an increase in the expression of the TGFB1 and its receptors ALK1 and endoglin, which are involved in the proliferation of Leydig cells. The aim of the present work was to analyze the expression of aromatase, estrogen and progesterone receptors (ERs, PR) in pathological testicular biopsies with SCO or H with and without LCH. The ERs and CYP19 proteins were detected in the Leydig cells from all pathological biopsies analyzed. Biopsies with SCO or H with LCH showed an increment in the immunostaining of CYP19 and ERs in the Leydig cells respect to biopsies without LCH. The gene expression of CYP19 was increased in SCO or H biopsies with LCH respect to SCO and H biopsies without LCH. PR was localized in Leydig cells and showed a significant increment in biopsies with LCH respect from biopsies without LCH. The gene expression of both PRA and PRB was increased in biopsies with LCH respect to biopsies without LCH. In concussion, alterations in the gene expression of aromatase, ERs, and PR and the likely interactions of these systems with locally produced factors such as growth factors and cytokines, might lead to Leydig cell proliferation in testicular pathology.

Polymorphism in the Regulatory Region of the Aromatase CYP19a Gene in Nile Tilapia

The aim of this study was to evaluate the polymorphism in a portion of the gene regulatory region for ovarian aromatase （CYP19a） in three strains of Tilapia, Oreochomis niloticus （Linnaeus） （GIFT--Genetically Improved Farmed Tilapia, Chitralada and Supreme）. A total of 90 animals per strain of Tilapia, Oreochromis niloticus （Linnaeus） were analysed. After DNA extraction, samples were subjected to PCR using primers designed to flank the region of interest encompassing the sites of transcription （WT1-KTS and SRY）. Samples were analyzed by PCR-SSCP and subsequently sequenced. Three polymorphisms were identified in this region, resulting in two different sequences, in the GIFT strain while no polymorphism was found in both Supreme and Chitralada strains. At the position - 1178 the substitution of a guanine for a cytosine, at the - 1081 the exchange of guanine for adenine and at the position -1 138 we found a SNP, possible site of heterozygosity. Even with polymorphisms in the target study area, when taking the three strains into account, one can assume that the portion of the regulatory region of the ovarian aromatase gene in the Supreme strain and Chitralada does not show polymorphism.

Experimental Sex Inversion of Chicken Embryos at Aromatase Inhibition, Estrogen Receptor Modulation, DNA Demethylation and Progesterone Treatment

The work was carried out by microinjections of an aromatase inhibitor letrozole, an estrogen receptor modulator tamoxifen in incubated eggs Gallus g. domesticus, the first day of incubation. It also used 5-azacytidine (5-AC) at the same time. Injection of progesterone was carried out before the onset of meiosis prophase 1 on 16 h of incubation. Morphologically and histologically and by PCR, sex of the 17-day embryos was controlled. According to information received microinjection of letrozole caused almost a 100% inversion of genetic males to females, which is manifested in the morphology of the gonads. In other experiments, sex reversal is not revealed. The results are obtained in this study, and the data suggest that the presence of gonadogenesis in female chickens makes earlier emergence of aromatase in the beginning of incubation, than that according to the classical scheme of sex determination in birds. Presumably this kind of synthesis is triggered by some W-chromosomal factors. It failed to detect the phenomenon of gender inversion—the transformation of males into females after exposure to demethylating agent 5-AC that casts doubt on the participation of male hypermethylated (MHM)-RNA-segment in regulating the activity of sex determining genes.

Association between mRNA Expression of Aromatase, 17β-HSD2, Level of TGF-β1 and Stage of Endometriosis

Aim: To identify the correlation between mRNA expression of aromatase, 17β-HSD2 level of TGF-β1 and stage of endometriosis. Methods: Case control study was done on 80 patients divided by 40 endometriosis patients and 40 patients as control. mRNA expression of aromatase, mRNA 17β-SD2, was checked using reverse-transcriptase polymerase chain reaction (RT-PCR) and TGF-β1 serum and peritoneal fluid was checked using ELISA. Result: Level of mRNA aromatase from ectopic and eutopic endometrium increased significantly compared to control group (p < 0.001). mRNA 17β-HSD2 expression is significantly lower compared to control (p TGF-β1 on endometriosis group was significantly higher compared to control group (p < 0.05). Level of peritoneal fluid TGF-β1 on endometriosis group was higher than control group (p < 0.001). There are no correlations between mRNA aromatase, type 2 17β-HSD, TGF-β1 serum level to endometriosis stage. There are significant correlations between peritoneal fluid TGF-β1 levels to endometriosis stage.

A systematic review and meta-analysis of clinical trials implementing aromatase inhibitors to treat male infertility

Aromatase activity has commonly been associated with male infertility characterized by testicular dysfunction with low serum testosterone and/or testosterone to estradiol ratio.In this subset of patients,and particularly in those with hypogonadism,elevated levels of circulating estradiol may establish a negative feedback on the hypothalamic–pituitary–testicular axis by suppressing follicle-stimulating hormone(FSH)and luteinizing hormone(LH)production and impaired spermatogenesis.Hormonal manipulation via different agents such as selective estrogen modulators or aromatase inhibitors to increase endogenous testosterone production and improve spermatogenesis in the setting of infertility is an off-label option for treatment.We carried out a systematic review and meta-analysis of the literature of the past 30 years in order to evaluate the benefits of the use of aromatase inhibitors in the medical management of infertile/hypoandrogenic males.Overall,eight original articles were included and critically evaluated.Either steroidal(Testolactone)or nonsteroidal(Anastrozole and Letrozole)aromatase inhibitors were found to statistically improve all the evaluated hormonal and seminal outcomes with a safe tolerability profile.While the evidence is promising,future prospective randomized placebo-controlled multicenter trials are necessary to better define the efficacy of these medications.

Effect of Yikun Neiyi Wan on the Expression of Aromatase P450,COX-2,and ER Related Receptor in Endometrial Cells in Vitro from Patients with Endometriosis

To investigate the effect of Yikun Neiyi Wan （益坤内异丸YKNYW） and gestrinone on the expression of aromatase P450 （P450arom）, cyclo-oxygenase-2 （COX-2） and estrogen receptor （ER） in isolated ectopic and normal endometriat stroma cells in vitro. Methods： Digestion and serial filtration were used to isolate and culture the ectopic and eutopic endometrial cells from patients with chocolate cyst in virto Transformation of the cell morphology was observed in a inverted microscope. The effect of YKNYW on the expression of aromatase P450, cyclo-oxygenase-2, estrogen receptor in cultured endometriosis cells were detected by immunohistochemical method. Results： The expression levels of P450arom, COX-2 in glandular epithelium cells in vitro were decreased significantly by YKNYW compared with gestrinone （P〈0.05）. ER expression in mesenchymal cells of endometriosis was increased by YKNYW in the large and medium dosage groups compared with gestrinone. Conclusion： The mechanism by which YKNYW alleviates endometriosis pain is possibly related to the decrease in ectopic endometrial P450 arom and COX-2 expression in glandular epithelium, contrary to gestrinone, and the increase in ER expression in mesenchymalis, consistent with gestrione in patients with endometriosis.

Effect of Jianpi Bushen formula on aromatase-inhibitor-associated bone loss after menopause

OBJECTIVE: To investigate the effect of Jianpi Bushen(JPBS) formula on aromatase inhibitor(AI)-associated bone loss after menopause.METHODS: Six-month-old female rats were randomly divided into 6 groups: a sham group, an ovariectomized(OVX) group, an OVX treated with exemestane and 3 OVX groups each treated with a different dose of JPBS formula. Bone mineral density(BMD) at the lumbar vertebrae, histology, bone markers and serum levels of estrogen were assessed. Furthermore, a cohort study was conducted in 130 postmenopausal women with breast cancer that had undergone treatment with AIs. The subjects were given JPBS + caltrate D or caltrate D only, administered orally. BMD at the lumbar vertebrae and femoral neck and bone markers were evaluated in both control and herbal treatment groups at baseline and 12 months.RESULTS: Experimental results indicated that a high dose of JPBS significantly increased the trabecular bone area percentage(Tb.Ar %) and broadened the trabecular thickness(Tb.Th). The JPBS formula enriched the carboxyterrninal propeptide of type ipmcollagen and increased serum estrogen level significantly. The clinical investigation revealed that bone loss was decreased in the group treated with JPBS vs control(BMD T score at lumbar vertebrae, 3.9% increased vs 14.58% decreased, respectively, P = 0.004 and BMD T score on femoral neck, 1.8% decreased vs 22.45% decreased, respectively, P = 0.008). Besides, JPBS formula elevated Nmiddle osteocalcin and decreased type Ⅰ collagen cross-linked C-terminal telopeptide.CONCLUSION: JPBS formula prevented aromatase-inhibitor-associated bone loss after menopause by inhibiting bone resorption and promoting bone formation.

Chinese Medicine Yishen Jiangu Granules(益肾健骨颗粒)on Aromatase Inhibitor-Associated Musculoskeletal Symptoms

Objective： To assess the effectiveness of Yishen Jiangu Granules（益肾健骨颗粒, YSJGG） on aromatase inhibitor-associated musculoskeletal symptoms（AIMSS）. Methods： A single-arm, open-label study was conducted in 34 postmenopausal women with breast cancer who experienced AIMSS. Patients were treated with YSJGG for 12 weeks（12.4 g orally twice daily）. The primary outcome was a change in the mean worst pain score of Brief Pain Inventory-Short Form（BPI-SF） over 12 weeks, and the second outcomes included changes in pain severity and pain-related interference of BPI-SF and Western Ontario and McMaster Universities Osteoarthritis Index（WOMAC）, Modified Score for the Assessment of Chronic Rheumatoid Affections of the Hands（M-SACRAH）, the Functional Assessment of Cancer Therapy-Breast（FACT-B）, bone mineral density（BMD） and blood indices such as calcium（Ca）, phosphate（P）, and alkaline phosphatase（ALP）. Results： Of 37 women recruited, 30 initiated the therapy and 24 were evaluable at 12 weeks. The primary outcome（BPI-SF worst pain scores） achieved a 2.17-point reduction compared with baseline（5.75±1.87 vs 3.58±2.15, P〈0.01）. There were reductions in pain severity（decreased 1.65, P〈0.01） and pain-related interference（decreased 2.55, P〈0.01）. The changes in WOMAC and M-SACRAH scores were similar to BPI-SF（P〈0.05）. In the FACT-B, only physical wel-being and functional wel-being were improved compared with baseline（P〈0.05）. No clinical differences were found in BMD, Ca, P and ALP. Conclusion： YSJGG is an effective and wel-tolerated agent to reduce AIMSS.

Estrogen and oxytocin involvement in social preference in male mice:a study using a novel long-term social preference paradigm with aromatase,estrogen receptor-αand estrogen receptor-β,oxytocin,and oxytocin receptor knockout male mice

Certain aspects of social behavior help animals make adaptive decisions during encounters with other animals.When mice choose to approach another conspecific,the motivation and preference behind the interaction is not well understood.Estrogen and oxytocin are known to influence a wide array of social behaviors,including social motivation and social preference.The present study investigated the effects of estrogen and oxytocin on social preference using aromatase(ArKO),estrogen receptor(ER)α(αERKO),ERβ(βERKO),oxytocin(OTKO),oxytocin receptor(OTRKO)knockout and their respective wild-type(WT)male mice.Mice were presented with gonadally-intact versus castrated male(IC),intact male versus ovariectomized female(IF),or intact male versus empty cage(IE)stimuli sets for 5 days.ArWT showed no preference for either stimuli in IC and IF and intact male preference in IE,but ArKO mice preferred a castrated male or an ovariectomized female,or had no preference for either stimulus in IC,IF and IE stimuli sets,respectively,suggesting reduced intact male preference.αandβWT mice preferred a castrated male,showed no preference,and preferred an intact male in IC,IF and IE,respectively.αERKO mice displayed similar modified social preference patterns as ArKO,whereas the social preference ofβERKO mice remained similar toβWT.OTWT preferred a castrated male whereas OTKO,OTRWT and OTRKO mice failed to show any preference in IC and none showed preference for either stimuli in IF.Collectively,these findings suggest that estrogen regulates social preference in male mice and that impaired social preference in oxytocin-deficient mice may be due to severe deficits in social recognition.

Cyclooxygenase-2 and the inflammogenesis of breast cancer

Cohesive scientific evidence from molecular, animal, and human investigations supports the hypothesis that constitutive overexpression of cyclooxygenase-2(COX-2) is a ubiquitous driver of mammary carcinogenesis, and reciprocally, that COX-2 blockade has strong potential for breast cancer prevention and therapy. Key findings include the following:(1) COX-2 is constitutively expressed throughout breast cancer development and expression intensifies with stage at detection, cancer progression and metastasis;(2) essential features of mammary carcinogenesis(mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, metastasis and immunosuppression) are linked to COX-2-driven prostaglandin E2(PGE-2) biosynthesis;(3) upregulation of COX-2 and PGE-2 expression induces transcription of CYP-19 and aromatase-catalyzed estrogen biosynthesis which stimulates unbridled mitogenesis;(4) extrahe-patic CYP-1B1 in mammary adipose tissue converts paracrine estrogen to carcinogenic quinones with mutagenic impact; and(5) agents that inhibit COX-2 reduce the risk of breast cancer in women without disease and reduce recurrence risk and mortality in women with breast cancer. Recent sharp increases in global breast cancer incidence and mortality are likely driven by chronic inflammation of mammary adipose and upregulation of COX-2 associated with the obesity pandemic. The totality of evidence clearly supports the supposition that mammary carcinogenesis often evolves as a progressive series of highly specific cellular and molecular changes in response to induction of constitutive overexpression of COX-2 and the prostaglandin cascade in the "inflammogenesis of breast cancer".

Current medical treatment of estrogen receptor-positive breast cancer

Approximately 80% of breast cancers(BC) are estrogen receptor(ER)-positive and thus endocrine therapy(ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of(1) ovarian function suppression(OFS), usually obtained using gonadotropinreleasing hormone agonists(Gn RHa);(2) selective estrogen receptor modulators or down-regulators(SERMs or SERDs); and(3) aromatase inhibitors(AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs(i.e., tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ, especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs(i.e., fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type Ⅰ are permanent steroidal inhibitors of aromatase, while type Ⅱ are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs(i.e., anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors(palbociclib) and mammalian target of rapamycin(m TOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness.

Estrogen deficiency leads to telomerase inhibition, telomere shortening and reduced cell proliferation in the adrenal gland of mice

Estrogen deficiency mediates aging, but the underlying mechanism remains to be fully determined. We report here that estrogen deficiency caused by targeted disruption of aromatase in mice results in significant inhibition of telomerase activity in the adrenal gland in vivo. Gene expression analysis showed that, in the absence of estrogen, telomerase reverse transcriptase （TERT） gene expression is reduced in association with compromised cell proliferation in the adrenal gland cortex and adrenal atrophy. Stem cells positive in c-kit are identified to populate in the parenchyma of adrenal cortex. Analysis of telomeres revealed that estrogen deficiency results in significantly shorter teiomeres in the adrenal cortex than that in wild-type （WT） control mice. To further establish the causal effects of estrogen, we conducted an estrogen replacement therapy in these estrogen-deficient animals. Administration of estrogen for 3 weeks restores TERT gene expression, telomerase activity and cell proliferation in estrogen-deficient mice. Thus, our data show for the first time that estrogen deficiency causes inhibitions of TERT gene expression, telomerase activity, telomere maintenance, and cell proliferation in the adrenal gland of mice in vivo, suggesting that telomerase inhibition and telomere shortening may mediate cell proliferation arrest in the adrenal gland, thus contributing to estrogen deficiency-induced aging under physiological conditions.

Neoadjuvant endocrine therapy: A potential strategy for ER-positive breast cancer

A potential strategy for patients with estrogen receptor(ER)-positive breast cancer is necessary to replace neoadjuvant chemotherapy which has limited benefit.Neoadjuvant endocrine therapy(NAE)has been indicated to be a favorable alternate approach to downstage large or locally advanced breast cancer in ER-positive,human epidermal growth factor receptor 2(HER2)-negative(ER+/HER2-)patients,especially postmenopausal women.Previous studies have demonstrated the efficacy of various endocrine agents in NAE.Aromatase inhibitors(AIs)have proven superiority over tamoxifen as a suitable choice to optimize treatment efficacy.Fulvestrant was recently reported as an effective agent,similar to AIs.Furthermore,the addition of targeted agents exerts synergistic antiproliferative effects with endocrine agents and rapidly improves response rates in both endocrine sensitive and resistant tumors.The neoadjuvant platform provides a unique opportunity to define the appropriate strategy and address the mechanisms of endocrine resistance.In addition,the predictive value of biomarkers and genomic assays in NAE is under investigation to evaluate individual effects and validate biomarker-based strategies.In this review,we discuss the most relevant evidence on the potential of NAE for ER+breast cancer.The current understanding also offers new insights into the identification of the optimal settings and valuable predictive tools of NAE to guide clinical treatment decisions and achieve beneficial therapeutic effects.

Management of genitourinary syndrome of menopause in breast cancer survivors:An update

There is increasing attention about managing the adverse effects of adjuvant therapy(Chemotherapy and anti-estrogen treatment)for breast cancer survivors(BCSs).Vulvovaginal atrophy(VVA),caused by decreased levels of circulating estrogen to urogenital receptors,is commonly experienced by this patients.Women receiving antiestrogen therapy,specifically aromatase inhibitors,often suffer from vaginal dryness,itching,irritation,dyspareunia,and dysuria,collectively known as genitourinary syndrome of menopause(GSM),that it can in turn lead to pain,discomfort,impairment of sexual function and negatively impact on multiple domains of quality of life(QoL).The worsening of QoL in these patients due to GSM symptoms can lead to discontinuation of hormone adjuvant therapies and therefore must be addressed properly.The diagnosis of VVA is confirmed through patient-reported symptoms and gynecological examination of external structures,introitus,and vaginal mucosa.Systemic estrogen treatment is contraindicated in BCSs.In these patients,GSM may be prevented,reduced and managed in most cases but this requires early recognition and appropriate treatment,but it is normally undertreated by oncologists because of fear of cancer recurrence,specifically when considering treatment with vaginal estrogen therapy(VET)because of unknown levels of systemic absorption of estradiol.Lifestyle modifications and nonhormonal treatments(vaginal moisturizers,lubricants,and gels)are the first-line treatment for GSM both in healthy women as BCSs,but when these are not effective for symptom relief,other options can be considered,such as VET,ospemifene,local androgens,intravaginal dehydroepiandrosterone(prasterone),or laser therapy(erbium or CO2 Laser).The present data suggest that these therapies are effective for VVA in BCSs;however,safety remains controversial and a there is a major concern with all of these treatments.We review current evidence for various nonpharmacologic and pharmacologic therapeutic modalities for GSM in BCSs and highlight the substantial gaps in the evidence for safe and effective therapies and the need for future research.We include recommendations for an approach to the management of GSM in women at high risk for breast cancer,women with estrogen-receptor positive breast cancers,women with triplenegative breast cancers,and women with metastatic disease.

Microenvironment and endocrine resistance in breast cancer:Friend or foe?

Breast cancer affects one in eight women around the world. Seventy five percent of these patients have tumors that are estrogen receptor positive and as a consequence receive endocrine therapy. However,about one third eventually develop resistance and cancer reappears. In the last decade our vision of cancer has evolved to consider it more of a tissuerelated disease than a cell-centered one. This editorial argues that we are only starting to understand the role the tumor microenvironment plays in therapy resistance in breast cancer. The development of new therapeutic strategies that target the microenvironment will come when we clearly understand this extremely complicated scenario. As such,and as a scientific community,we have extremely challenging work ahead. We share our views regarding these matters.