The menopause,hormone replacement therapy and breast cancer

Concern exists that the reduction in breast cancer risk associated with the onset of the menopause will be negated with exposure to hormone replacement therapy (HRT). Evidence from large-scale randomised HRT trials support observational data that have shown a modest increase in breast cancer risk with long-term use (i.e. >15 years) of combined therapy, although this falls following HRT cessation suggesting a growth-promoting effect. Randomised evidence demonstrates that the efficacy of anti-estrogens, aromatase inhibitors and raloxifene in the treatment and chemoprevention of breast cancer are restricted to women with oestrogen receptor positive (ER +ve) disease; however, HRT has not been associated conclusively with a predominance of hormone sensitive breast cancer. Despite stimulating the breast cancer cell growth, HRT has not been shown to increase breast cancer recurrence or mortality when prescribed to breast cancer survivors experiencing oestrogen deficiency symptoms and randomised trials have been recommended and commenced. In conjunction with controlled breast cancer trials demonstrating a therapeutic benefit of high dose estrogens and interest in the use of additive oestrogen therapy in patients developing resistance to oestrogen deprivation, the dogma that HRT is an absolute contra-indication following diagnosis is challenged.     

A role of SIPL1/SHARPIN in promoting resistance to hormone therapy in breast cancer

SIPL1 inhibits PTEN function and stimulates NF-κB signaling; both processes contribute to resistance to hormone therapy in estrogen receptor positive breast cancer (ER + BC). However, whether SIPL1 promotes tamoxifen resistance in BC remains unclear. We report here that SIPL1 enhances tamoxifen resistance in ER + BC. Overexpression of SIPL1 in MCF7 and TD47 cells conferred tamoxifen resistance. In MCF7 cell-derived tamoxifen resistant (TAM-R) cells, SIPL1 expression was upregulated and knockdown of SIPL1 in TAM-R cells re-sensitized the cells to tamoxifen. Furthermore, xenograft tumors produced by MCF7 SIPL1 cells but not by MCF7 empty vector cells resisted tamoxifen treatment. Collectively, we demonstrated a role of SIPL1 in promoting tamoxifen resistance in BC. Increases in AKT activation and NF-κB signaling were detected in both MCF7 SIPL1 and TAM-R cells; using specific inhibitors and unique SIPL1 mutants to inhibit either pathway significantly reduced tamoxifen resistance. A SIPL1 mutant defective in activating both pathways was incapable of conferring resistance to tamoxifen, showing that both pathways contributed to SIPL1-derived resistance to tamoxifen in ER + BCs. Using the Curtis dataset of breast cancer (n = 1980) within the cBioPortal database, we examined a correlation of SIPL1 expression with ER + BC and resistance to hormone therapy. SIPL1 upregulation strongly associates with reductions in overall survival in BC patients, particularly in patients with hormone naïve ER + BCs. Taken together, we provide data suggesting that SIPL1 contributes to promote resistance to tamoxifen in BC cells through both AKT and NF-κB actions.     

The effects of hormone therapy on cognition in breast cancer

The use of hormonal therapies for the treatment of breast cancer is common, yet few studies have examined the possible cognitive effects. Several regions of the brain, important in memory and cognition, are rich in oestrogen receptors. As a result, the long-term use of anti-oestrogens may have potential consequences for cognition. This project aims to establish whether significant cognitive deficit exists in women receiving hormone therapy for breast cancer and to develop a cognitive package that is sensitive to the potential effects of oestrogen deficiency on cognition. Cognitive assessments measured a range of memory and attention functions in patient and control groups to identify whether cognitive impairment, if apparent, occurs at a widespread or function specific level. Ninety-four patients from the anastrozole, tamoxifen and combined (ATAC) trial and 35 non-cancer controls were assessed. Groups did not differ significantly in age or estimated full-scale intelligence. The patient group did not differ from controls on measures of working memory, attention and visual memory but was significantly impaired compared to the control group on measures of verbal memory (P=0.026) and processing speed (P=0.032). Cognitive performance in the patient group was not significantly related to length of time on trial or measures of psychological morbidity. As more and more hormonal agents are used in clinical trials of both adjuvant and preventive settings it is of vital importance that any potentially deleterious effects on cognitive function are measured adequately. Preliminary results from this study suggest that anti-oestrogen therapy may cause a specific deficit in verbal memory that corroborates the links between oestrogen levels and verbal memory often reported in studies of the cognitive benefits of hormone replacement therapy.     

Pharmacogenetics of hormone replacement therapy for climacteric symptoms

Hormone replacement therapy (HRT) is highly effective for women suffering from climacteric symptoms, with occasionally severe side effects. To determine which women needs HRT for climacteric symptoms indeed, pharmacogenetical approach for HRT was performed. Under the condition of minimal HRT, 33 patients required HRT for more than 1 year and the remaining 156 did not. Three single nucleotide polymorphisms (SNPs) in estrogen receptor α (ERα) gene and 3 SNPs and a microsatellite polymorphism in estrogen receptor β (ERβ) gene were analyzed using LightTyper and PCR. Homozygous for 18 CA repeats of D14S1026 (OR 8.00, 95% CI 2.56-25.02, P < 0.001) and rs1256049 (OR 6.35, 95% CI 2.38-16.92, P = 0.004) in ERβ associated with minimal HRT. In contrast, rs1271572 in 789 bp upstream region of ERβ (OR 0.30, 95% CI 0.14-0.65, P = 0.002) gene decreased HRT. rs2228480 in ERα gene also increased HRT. Tailored decisions can be expected on the future use of HRT referring genetic polymorphisms of individuals.     

Hysterectomy and risk of epithelial ovarian cancer by histologic type,endometriosis, and menopausal hormone therapy

BackgroundThis nationwide, register-based case-control study investigated the association between hysterectomy and risk of epithelial ovarian cancer according to histology and by history of endometriosis and menopausal hormone therapy (MHT) use.MethodsFrom the Danish Cancer Registry, all women registered with epithelial ovarian cancer at age 40–79 years during 1998–2016 were identified (n = 6738). Each case was sex- and age-matched to 15 population controls using risk-set sampling. Information on previous hysterectomy on benign indication and potential confounders was retrieved from nationwide registers. Conditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between hysterectomy and ovarian cancer according to histology, endometriosis, and use of MHT.ResultsHysterectomy was not associated with risk of epithelial ovarian cancer overall (OR=0.99; 95% CI 0.91 –1.09) but was associated with reduced risk of clear cell ovarian cancer (OR=0.46; 95% CI 0.28–0.78). In stratified analyses, decreased ORs associated with hysterectomy were seen in women with endometriosis (OR=0.74; 95% CI 0.50–1.10) and in non-users of MHT (OR=0.87; 95% CI 0.76–1.01). In contrast, among long-term MHT users, hysterectomy was associated with increased odds for ovarian cancer (OR=1.20; 95% CI 1.03–1.39).ConclusionHysterectomy was not associated with epithelial ovarian cancer overall but with reduced risk of clear cell ovarian cancer. Our findings may suggest a reduced risk of ovarian cancer after hysterectomy in women with endometriosis and in MHT non-users. Interestingly our data pointed to an increased ovarian cancer risk associated with hysterectomy among long-term users of MHT.     

MicroRNA replacement therapy in cancer

Despite the recent progress in cancer management approaches, the mortality rate of cancer is still growing and there are lots of challenges in the clinics in terms of novel therapeutics. MicroRNAs (miRNA) are regulatory small noncoding RNAs and are already confirmed to have a great role in regulating gene expression level by targeting multiple molecules that affect cell physiology and disease development. Recently, miRNAs have been introduced as promising therapeutic targets for cancer treatment. Regulatory potential of tumor suppressor miRNAs, which enables regulation of entire signaling networks within the cells, makes them an interesting option for developing cancer therapeutics. In this regard, over recent decades, scientists have aimed at developing powerful and safe targeting approaches to restore these suppressive miRNAs in cancerous cells. The present review summarizes the function of miRNAs in tumor development and presents recent findings on how miRNAs have served as therapeutic agents against cancer, with a special focus on tumor suppressor miRNAs (mimics). Moreover, the latest investigations on the therapeutic strategies of miRNA delivery have been presented.     

Reproductive factors,exogenous hormone use,and risk of pancreatic cancer in postmenopausal women

IntroductionThe epidemiologic literature on menstrual and reproductive factors associated with pancreatic cancer has yielded weak and inconsistent evidence of an association. Furthermore, few cohort studies have examined the association of exogenous hormone use, including type and duration, with this disease. The aim of this study was to assess the association of these exposures with risk of pancreatic cancer in a large cohort of postmenopausal women.MethodsWe used data from the Women’s Health Initiative on 1003 cases of pancreatic cancer diagnosed among 158,298 participants over 14.3 years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the associations of interest.ResultsBeing parous vs. nulliparous was associated with reduced risk (HR = 0.84, 95% CI 0.70–1.00), and women who had 1–2 and 3–4 births were at decreased risk compared to nulliparous women, whereas women who had >5 births showed no decrease in risk. Compared to women who gave birth between the ages of 20–29, women who gave birth at age 30 or above were at increased risk (HR 1.23, 95% CI 1.00–1.53, p for trend 0.003). Other reproductive factors and exogenous hormone use were not associated with risk.ConclusionsTogether with the existing literature on this topic, our results suggest that reproductive and hormonal exposures are unlikely to play an important role in the etiology of pancreatic cancer.     

The effect of hormone therapy on olfactory sensitivity is dependent on apolipoprotein E genotype

Patients with Alzheimer's disease (AD) show a deficit in olfactory threshold sensitivity. The Apolipoprotein E (ApoE) 4 allele is associated with increased risk of AD and earlier symptom onset. Hormone therapy (HT) may exert neuroprotective effects on brain areas affected by AD. The current study investigated the effect of HT on performance on an olfactory threshold test in 4 positive and 4 negative non-hysterectomized, non-demented, elderly females and AD patients. Among the non-demented participants, 4 positive females who had received HT performed 1) significantly better than those without HT, and 2) at levels similar to those of 4 negative females. In contrast, those without HT who were 4 positive performed significantly worse than those who were 4 negative. HT had no effect on performance in AD patients regardless of 4 status. These results suggest that HT may offer protection against loss of olfactory function in 4 positive individuals in preclinical stages of AD. Future research is warranted in order to investigate further the neuroprotective role of HT on sensory and cognitive functions in non-demented aging individuals.     

Type 2 diabetes,obesity, and breast cancer risk among Japanese women of the atomic bomb survivor cohort

BackgroundMuch less is known about diabetes than obesity as a predictor of breast cancer incidence and most previous studies have been conducted in white populations. Therefore, this project within the Radiation Effects Research Foundation’s cohort of Japanese atomic bomb survivors aimed to determine the independent contributions of obesity and diabetes to develop breast cancer.MethodsAfter excluding women with unknown A-bomb radiation dose, a radiation dose of ≥100 mGy, a pre-existing history of breast cancer, and missing body mass index (BMI), the analysis included 29,818 women. Breast cancer status and deaths until 2009 were identified from cancer registries and vital records. Cox regression with age as the time metric was applied to estimate hazard ratios (HR) and 95% confidence intervals (CI) for BMI and diabetes status as time-varying exposures alone and in combination while adjusting for known confounders.ResultsDiabetes prevalence increased from 2.6% to 5.3% and 7.5% from the first to the second and third data collection. During 27.6 ± 12.2 years of follow-up, 703 women had developed breast cancer (mean age of 66.0 ± 12.9 years) and 31 (4.4%) had been diagnosed with diabetes. A diagnosis of diabetes was not significantly associated with breast cancer incidence without (HR 1.12, 95% CI 0.77–1.64) and with BMI (HR 1.01, 95% CI 0.69–1.49) as a covariate. The respective HRs for overweight and obesity were 1.61 (95% CI 1.34–1.93) and 2.04 (95% CI 1.40–2.97).ConclusionsAmong a long-time Japanese cohort, excess body weight but not a diabetes diagnosis was significantly associated with breast cancer risk.     

miRNA-143 replacement therapy harnesses the proliferation and migration of colorectal cancer cells in vitro

miR-143 is a tumor suppressor miRNA which its downregulation is frequently reported in colorectal cancer (CRC). This miRNA is a negative regulator of K-RAS, c-MYC, BCL-2, and MMP-9 genes which are engaged in tumor growth and metastasis. In the present study, miR-143 restoration was performed by transfection of the pCMV-miR-143 vector into the SW-480 CRC cells. Subsequently, alterations in proliferative and migratory potential of the cells were investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and wound-healing assays, respectively. Moreover, to detect apoptosis incidence in the transfected cells, 4',6-diamidino-2-phenylindole (DAPI) staining was used. Furthermore, mRNA levels of c-MYC, K-RAS, MMP-9, and BCL-2, as potential targets of miR-143, were assessed by quantitative Real-Time PCR (qRT-PCR). Also the expression levels of c-MYC, K-RAS, and MMP-9 proteins were investigated by the western blot analysis. Finally, the ratio of BAX to BCL-2 expression, as a potential marker of the response to apoptosis stimuli, was compared between the control and test groups. Furthermore, the trypan blue test was performed to determine the cell viability in cell suspension. According to the results, a decreased viability and migratory potential was observed for the miR-143 receiving cells. The DAPI staining also confirmed the occurrence of apoptosis. Moreover, BCL-2, K-RAS, MMP-9, and c-MYC mRNAs were significantly downregulated in the miR-143 grafted cells. The BAX/BCL-2 ratio also indicated a notable increase in the cells with miR-143 overexpression. In brief, miR-143 replacement could be considered as an effective strategy for the management of CRC and attenuating its invasive features.     

ZDHHC22-mediated mTOR palmitoylation restrains breast cancer growth and endocrine therapy resistance

Palmitoylation is essential for the classic hallmarks of cancers through regulating protein stability and protein-protein interactions. ZDHHC22, as a well-known member of palmitoyltrans-ferase family, its role has not been revealed in cancer. We found ZDHHC22 expression was significantly lower in estrogen receptor (ER) negative breast cancer (BrCa) tissues and cell lines, and its expression was positively corelated with the clinical prognosis of BrCa patients. The lower expression of ZDHHC22 might be caused by its promoter methylation. ZDHHC22 inhibited the proliferation capability of BrCa cells both in vitro and in vivo, depending on its encoding palmitoyltransferase activity. In terms of the mechanisms, ZDHHC22 reduced mTOR stability via palmitoylation and decreased the activation of the AKT signaling pathway. Furthermore, ectopic expression of ZDHHC22 could restore the sensitivity to tamoxifen therapy in MCF-7R cells. Collectively, ZDHHC22 may serve as a prognostic biomarker and therapeutic target, providing the theoretical foundation for exploring specific palmitoylation drugs targeted, especially for endocrine therapy-resistant BrCa patients.     

Effect of postmenopausal hormone replacement therapy on lipoprotein and homocysteine levels in Chinese women

Epidemiological studies have revealed that postmenopausal estrogen replacement therapy results in a marked reduction in the risk for cardiovascular diseases. In the present study, we evaluated plasma lipoprotein profile as well as homocysteine levels in 145 postmenopausal and premenopausal Chinese women living in Hong Kong. We also investigated the effect of hormonereplacement therapy (HRT) with estrogen or estrogen combined with progestin on plasma lipoprotein profile and homocysteine concentrations in those individuals. Postmenopausal women displayed significantly higher plasma levels of total cholesterol, LDLcholesterol and apoB as well as higher plasma homocysteine levels than that of premenopausal women. HRT with either estrogen (17-estradiol or conjugated equine estrogen) alone or estrogen combined with progestin for 3.5–4.5 years significantly improved the lipoprotein profile in postmenopausal women by decreasing the levels of total cholesterol (12–20% reduction), LDL-cholesterol (26–29% reduction) and apoB (21–25% reduction). In women treated with 17estradiol or conjugated equine estrogens their plasma levels of apoAI were significantly elevated (18% elevation) as compared to non-users. HRT also reduced plasma concentrations of homocysteine (13–15% reduction). In conclusion, we found that long-term HRT was associated with improvement in plasma lipoprotein profile and a reduction in homocysteine concentration in postmenopausal women. These results support the notion that the improvement of lipoprotein profile and a reduction in homocysteine concentration may contribute to the beneficial effect of HRT on cardiovascular risk.     

Cancer risk after breast proton therapy considering physiological and radiobiological uncertainties

BackgroundThe reduced normal tissue dose burden from protons can reduce the risk of second cancer for breast cancer patients. Breathing motion and the impact of variable relative biological effectiveness (RBE) are however concerns for proton dose distributions. This study aimed to quantify the impact of these factors on risk predictions from proton and photon therapy.Materials and methodsTwelve patients were planned in free breathing with protons and photons to deliver 50 Gy (RBE) in 25 fractions (assuming RBE = 1.1 for protons) to the left breast. Second cancer risk was evaluated with several models for the lungs, contralateral breast, heart and esophagus as organs at risk (OARs). Plans were recalculated on CT-datasets acquired in extreme phases to account for breathing motion. Proton plans were also recalculated assuming variable RBE for a range of radiobiological parameters.ResultsThe OARs received substantially lower doses from protons compared to photons. The highest risks were for the lungs (average second cancer risks of 0.31% and 0.12% from photon and proton plans, respectively). The reduced risk with protons was maintained, even when breathing and/or RBE variation were taken into account. Furthermore, while the total risks from the photon plans were seen to increase with the integral dose, no such correlation was observed for the proton plans.ConclusionsProtons have an advantage over the photons with respect to the induction of cancer. Uncertainties in physiological movements and radiobiological parameters affected the absolute risk estimates, but not the general trend of lower risk associated with proton therapy.     

Cardiovascular, anthropometric and neurocognitive features of healthy postmenopausal women: effects of hormone replacement therapy

Randomized clinical trials have not shown long-term benefit of postmenopausal hormone replacement therapy (PHT) nor have they shown conclusively that the harmful consequences outweighs the benefits of the treatment. Rather, it is possible that an individualized hormone replacement therapy in questionably clinically healthy postmenopausal women may lead to different results than randomized trials. DESIGN: In this cross-sectional study we evaluated anthropometric parameters, body composition, serum lipids, blood pressure, heart rate variability (HRV) and neurocognitive functions in 39 healthy postmenopausal women PHT users or not users (n=13, age 53.0+/-3.3 and n=26, age=53.3+/-5.0 SD, respectively) as well as in 27 younger controls (ages=33.3+/-7.1). RESULTS: Demographic parameters were similar in women PHT users and not users. Postmenopausal women showed a significantly increase of body mass index (BMI) as well as of waist circumference, compared to younger controls, but in PHT users the values of fat free mass were intermediate between the ones of not treated and younger women. The study of HRV showed a reduction in low frequency (LF) component (sympathetic modulation) during the day, and a reduction in high frequency (HF) component (parasympathetic modulation), particularly in postmenopausal women without PHT. PHT users were characterized by autonomic parameters intermediate between younger controls and age-matched women without PHT. CONCLUSIONS: The impact of PHT on the age-dependent changes of anthropometric features and body composition seems to be modest but positive. Furthermore, PHT seems to play a positive role on the autonomic modulation of cardiac function, through a shift of LF/HF ratio values towards those of young controls.     

Advance in metabolism and target therapy in breast cancer stem cells

Breast cancer, like many other cancers, is believed to be driven by a population of cells that display stem cell properties. Recent studies suggest that cancer stem cells (CSCs) are essential for tumor progression, and tumor relapse is thought to be caused by the presence of these cells. CSC-targeted therapies have also been proposed to overcome therapeutic resistance in breast cancer after the traditional therapies. Additionally, the metabolic properties of cancer cells differ markedly from those of normal cells. The efficacy of metabolic targeted therapy has been shown to enhance anti-cancer treatment or overcome therapeutic resistance of breast cancer cells. Metabolic targeting of breast CSCs (BCSCs) may be a very effective strategy for anti-cancer treatment of breast cancer cells. Thus, in this review, we focus on discussing the studies involving metabolism and targeted therapy in BCSCs.     

Mammographic density and hormone receptor expression in breast cancer: the Multiethnic Cohort Study

Background: It is unclear whether mammographic breast density, a strong risk factor for breast cancer, predicts subtypes of breast cancer defined by estrogen receptor (ER) and/or progesterone receptor (PR) expression. Methods: In a nested case–control study, we compared the breast density of 667 controls and 607 breast cancer cases among women of Caucasian, Japanese, and Native Hawaiian ancestry in the Hawaii component of the Multiethnic Cohort Study. A reader blinded to disease status performed computer assisted density assessment on prediagnostic mammograms. Receptor status was obtained from the statewide Hawaii Tumor Registry. Tumors were classified into ER+PR+ (n = 341), ER−PR− (n = 50), ER+PR−/ER−PR+ (n = 64), and unstaged/unknown (n = 152). Mean percent density values were computed for women with more than one mammogram. Polytomous logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) while adjusting for confounders. Results: Mean percent density was significantly greater for ER+PR+ but not for ER−PR− tumors compared to controls after adjusting for age: 37.3%, 28.9% versus 29.4%, respectively. The overall OR per 10% increase in percent density were similar for ER+PR+ and ER+PR−/ER−PR+ tumors: 1.26 (95% CI 1.17–1.36) and 1.23 (95% CI 1.07–1.42), respectively. However, percent density was not found to be a predictor for ER−PR− tumors (OR 1.00, 95% CI 0.84–1.18). The results did not differ by ethnicity, nor by menopausal status, parity, or HRT use. Conclusions: Our findings indicate that within a multiethnic population, women with higher breast density have an increased risk for ER+PR+ but not ER−PR− tumors.     

Radiation therapy for bone-only metastases in breast cancer patients: A GOCO survey of current clinical practice

IntroductionThe role of radiation therapy (RT) for patients with bone-only metastatic (BOM) breast cancer has not been investigated sufficiently. The aim of this survey was to evaluate current clinical practice in treating breast cancer patients with BOM in Radiation Therapy Departments in Catalonia and Occitania within the scope of the GOCO group.Materials and methodsAn electronic questionnaire was completed by experienced radiation oncologists from fourteen RT centers. The items surveyed the professional experience, therapeutic approach, technique, dose stereotactic body RT (SBRT) availability.ResultsAll Radiation Oncology Departments (ROD) in Catalonia (12) and Occitania (2) responded to the survey. Eleven (78.5%) of the RODs advise RT for BOM as initial treatment in the oligometastatic setting. RT to asymptomatic bone oligometastases is more often restricted for “risky lesions”. The most inconsistent approaches were the treatment for asymptomatic lesions, when to treat bone metastases with respect to systemic treatment (ST) and the indication for RT after a complete response to ST.ConclusionWhile BOM breast cancer patients have a relatively good prognosis, there is a lack of consistency in their approach with RT. This can be explained by the absence of evidence-based guidelines and an incomplete availability of SBRT.     

Steroid sulphatase inhibitors for breast cancer therapy

In contrast to aromatase inhibitors, which are now in clinical use, the development of steroid sulphatase (STS) inhibitors for breast cancer therapy is still at an early stage. STS regulates the formation of oestrone from oestrone sulphate (E1S) but also controls the hydrolysis of dehydroepiandrosterone sulphate (DHEA-S). DHEA can be reduced to 5-androstenediol (Adiol), a steroid with potent oestrogenic properties. The active pharmacophore for potent STS inhibitors has now been identified, i.e. a sulphamate ester group linked to an aryl ring. This has led to the development of a number of STS inhibitors, some of which are due to enter Phase I trials in the near future. Such first generation inhibitors include the tricyclic coumarin-based 667 COUMATE. Aryl sulphamates, such as 667 COUMATE, are taken up by red blood cells (rbc), binding to carbonic anhydrase II (CA II), and transit the liver without undergoing first-pass inactivation. 667 COUMATE is also a potent inhibitor of CA II activity with an IC₅₀ of 17 nM. Second generation STS inhibitors, such as 2-methoxyoestradiol bis-sulphamate (2-MeOE2bisMATE), in addition to inhibiting STS activity, also inhibit the growth of oestrogen receptor negative (ER⁻) tumours in mice and are anti-angiogenic. As the active pharmacaphores for the inhibition of aromatase and STS are now known it may be possible to develop third generation inhibitors that are capable of inhibiting the activities of both enzymes. Whilst exploring the potential of such a strategy it was discovered that 667 COUMATE possessed weak aromatase inhibitory properties with an IC₅₀ of 300 nM in JEG-3 cells. The identification of potent STS inhibitors will allow the therapeutic potential of this new class of drug to be explored in post-menopausal women with hormone-dependent breast cancer. Second generation inhibitors, such as 2-MeOE2bisMATE, which also inhibit the growth of ER⁻ tumours should be active against a wide range of cancers.