Antiestrogenic Drug Research Articles

Loss of ERα involved-HER2 induction mediated by the FOXO3a signaling pathway in fulvestrant-resistant breast cancer

Patients with estrogen receptor alpha (ERα)-positive breast cancer are commonly treated with anti-estrogen drugs as an initial treatment strategy. Fulvestrant, an estrogen receptor antagonist, effectively blocks ERα signaling; however, long-term fulvestrant treatment induces drug resistance in the absence of ERα. In this study, we investigated the molecular mechanism underlying the loss of ERα, FOXO3a, and induction of HER2 in fulvestrant-resistant breast cancer. Short-term fulvestrant treatment degraded ERα proteins via the ubiquitin-proteasome degradation pathway in MCF7 cells. MCF7 cells turn into highly proliferative cells (fulvestrant-resistant cells: Ful-R) after long-term fulvestrant treatment. These cells exhibit markedly suppressed estrogen and progesterone receptor levels. The phosphorylation of EGFR, HER2, and ERK was induced in Ful-R, and these phosphorylation inhibitors suppressed cell proliferation in Ful-R. FOXO3a, a transcriptional regulator of ERα was decreased in Ful-R, and a ubiquitin-proteasome inhibitor restored the expression of FOXO3a. These results suggest that the suppression of FOXO3a and ERα led to the increased expression of TGF-α, EGFR, and HER2 and subsequent cell proliferation in Ful-R. This study highlights the potential development of therapeutic drugs targeting FOXO3a for the treatment of HER2-positive, estrogen, and progesterone receptor-negative her2-type proliferative breast cancers.

Breast cancers that disseminate to bone marrow acquire aggressive phenotypes through CX43-related tumor-stroma tunnels.

Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by direct contact. Protein-protein interaction networks revealed the rich connectome between 'borrowed' and 'intrinsic' components. Bioinformatics prioritized one of the 'borrowed' components, CCDC88A/GIV, a multi-modular metastasis-related protein that has recently been implicated in driving a hallmark of cancer, growth signaling autonomy. MSCs transferred GIV protein to ER+ breast cancer cells (that lack GIV) through tunnelling nanotubes via connexin (Cx)43-facilitated intercellular transport. Reinstating GIV alone in GIV-negative breast cancer cells reproduced approximately 20% of both the 'borrowed' and the 'intrinsic' gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC→tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.

Breast Cancers That Disseminate to Bone Marrow Acquire Aggressive Phenotypes through CX43-related Tumor-Stroma Tunnels.

Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by direct contact. Protein-protein interaction networks revealed the rich connectome between 'borrowed' and 'intrinsic' components. Bioinformatics prioritized one of the 'borrowed' components, CCDC88A /GIV, a multi-modular metastasis-related protein that has recently been implicated in driving a hallmark of cancer, growth signaling autonomy. MSCs transferred GIV protein to ER+ breast cancer cells (that lack GIV) through tunnelling nanotubes via connexin (Cx)43-facilitated intercellular transport. Reinstating GIV alone in GIV-negative breast cancer cells reproduced ∼20% of both the 'borrowed' and the 'intrinsic' gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC→tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.

Characterization of ERα Signaling to Cell Proliferation Induced by Chronic and Pulsatile E2 Stimulation in 2D and 3D Cell Cultures.

17β-estradiol is a hormone that plays a vital role in human physiology. It acts through estrogen receptors, specifically estrogen receptor α and estrogen receptor β, and its action is determined by the pulsatile secretion in the bloodstream. 17β-estradiol affects cell proliferation, and dysregulation of 17β-estradiol:estrogen receptor α signaling contribute to the development of breast cancer. Previous research on 17β-estradiol:estrogen receptor α signaling has primarily used two-dimensional cell cultures, which do not fully recapitulate the complexity of tumors that exist in a three-dimensional environment and do not consider the pulsatile nature of this hormone. To address these limitations, we studied 17β-estradiol:estrogen receptor α signaling in cell proliferation using both two-dimensional and three-dimensional breast cancer cell culture models under continuous and pulsatile stimulation conditions. Results revealed that breast cancer cells grown in an alginate-based three-dimensional matrix exhibited similar responsiveness to 17β-estradiol compared with cells grown in conventional two-dimensional culture plates. 17β-estradiol induced the expression of proteins containing estrogen response element in the three-dimensional model. The efficacy of the antiestrogen drugs fulvestrant (ICI182,280) and 4OH-tamoxifen was also demonstrated in the three-dimensional model. These results support the use of the three-dimensional culture model for studying tumor response to drugs and provide a more realistic microenvironment for such studies. Furthermore, the study revealed that a brief 5-min exposure to 17β-estradiol triggered a physiological response comparable with continuous hormone exposure, suggesting that the cellular response to 17β-estradiol is more important than the continuous presence of the hormone. In conclusion, the study demonstrates that the alginate-based three-dimensional culture model is suitable for studying the effects of 17β-estradiol and antiestrogen drugs on breast cancer cells, offering a more realistic representation of tumor-microenvironment interactions. The results also highlight the importance of considering the physiological importance of the temporal dynamics in studying 17β-estradiol signaling and cellular responses.

Study on the efficacy and toxicity of pamiparib combined with tamoxifen in the treatment of patients with epithelial ovarian cancer with biochemical recurrence during first-line PARPi maintenance therapy.

TPS5621 Background: A high proportion of ovarian cancer patients tend to have elevated CA-125 1-6 months before imaging recurrence. The time between biochemical recurrence (i.e., only elevated CA-125 without imaging finding or clinical symptoms) to imaging recurrence can be considered a "window period", and if the “window period” can be extended, it may convert platinum-resistant relapsed patients to platinum-sensitive patients, and ultimately improving patient outcomes. The timing of treatment for the biochemical recurrent patients has been controversial. Tamoxifen, an anti-estrogenic drug, is considered an effective option for these patients. Pamiparib (BGB-290) is an investigational small molecule inhibitor of PARP1 and PARP2. According to OReO study(NCT03106987), the "PARPi after PARPi" strategy is effective in recurrent ovarian cancer patients previously treated with a PARP inhibitor. Therefore, we aim to further explore the use of PARP inhibitors in maintenance therapy for patients with ovarian cancer. Methods: This study (NCT05669768) will evaluate the efficacy and toxicity of pamiparib and tamoxifen in ovarian cancer patients with biochemical recurrence during first-line PARPi maintenance therapy. The included ovarian cancer patients are required to achieve No Evidence of Disease (NED) or demonstrated a response following platinum-based chemotherapy, with normalized CA-125 levels. First-line maintenance treatment with a PARP inhibitor is mandatory, with a minimum interval of ≥6 months to biochemical recurrence. The trial design is interventional, employing a Simon two-stage design to estimate sample size. The primary outcome of the study is the CA-125 response rate, which was assessed according to the GCIG criteria.1 The secondary outcome was Time to First Subsequent Therapy (TFST). Patients undergo regular assessments for tumor markers and imaging throughout treatment. If persistent elevation of tumor markers or the detection of recurrent lesions or distant metastases is observed, the patient is promptly removed from the study group. Standardized antitumor therapy is then initiated based on the patient's condition. The total planned enrollment is 46 participants, utilizing a single-group assignment and an open-label design. 1 of planned 12 patients for the first stage of accrual have been enrolled. Reference: 1. Rustin GJ, Vergote I, Eisenhauer E, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer. 2011;21(2):419-423. Clinical trial information: NCT05669768 .

Genistein-Chitosan Derivative Nanoparticles for Targeting and Enhancing the Anti-Breast Cancer Effect of Tamoxifen In Vitro

Tamoxifen (TAM) is a classical anti-estrogenic drug that antagonizes estrogen by competitively binding to estrogen receptor α (ERα). However, drug resistance to TAM remains a significant challenge in breast cancer treatment. In this study, we aimed to design an actively targeted drug delivery system to enhance the proliferation inhibitory effects of TAM on ER positive breast cancer cells. Herein, chitosan (CS) was modified with genistein (GEN) to obtain the actively targeted GEN-CS. The TAM-loaded nanoparticles (TAM-GEN-CS-NPs) were constructed using an ionic-crosslinking method, with GEN-CS as the carrier material and sodium tripolyphosphate (TPP) as the crosslinking agent. As a result, TAM-GEN-CS-NPs exhibited a spherical morphology with an average size of 299.8 nm. The encapsulation efficiency and drug loading content were 85.77% and 14.13 µg/mg, respectively. Compared with free TAM, TAM-GEN-CS-NPs displayed obvious slow-release performance. In vitro cellular assays demonstrated that TAM-GEN-CS-NPs had active targeting and proliferation inhibitory effects on MCF-7 cells. The IC50 of TAM and TAM-GEN-CS-NPs were 10.25 µg/mL and 7.22 µg/mL, respectively. More importantly, the combination index (CI) value of TAM and GEN was less than 1, indicating synergistic effects. Therefore, TAM-GEN-CS-NPs hold the potential to enhance TAM therapy for breast cancer through active targeting and synergistic treatment strategies.

Rational evolution for altering the ligand preference of estrogen receptor alpha.

Estrogen receptor α is commonly used in synthetic biology to control the activity of genome editing tools. The activating ligands, estrogens, however, interfere with various cellular processes, thereby limiting the applicability of this receptor. Altering its ligand preference to chemicals of choice solves this hurdle but requires adaptation of unspecified ligand-interacting residues. Here, we provide a solution by combining rational protein design with multi-site-directed mutagenesis and directed evolution of stably integrated variants in Saccharomyces cerevisiae. This method yielded an estrogen receptor variant, named TERRA, that lost its estrogen responsiveness and became activated by tamoxifen, an anti-estrogenic drug used for breast cancer treatment. This tamoxifen preference of TERRA was maintained in mammalian cells and mice, even when fused to Cre recombinase, expanding the mammalian synthetic biology toolbox. Not only is our platform transferable to engineer ligand preference of any steroid receptor, it can also profile drug-resistance landscapes for steroid receptor-targeted therapies.

A Novel Metastatic Estrogen Receptor-Expressing Breast Cancer Model with Antiestrogen Responsiveness.

Most women diagnosed with breast cancer (BC) have estrogen receptor alpha-positive (ER+) disease. The current mouse models of ER+ BC often rely on exogenous estrogen to encourage metastasis, which modifies the immune system and the function of some tissues like bone. Other studies use genetically modified or immunocompromised mouse strains, which do not accurately replicate the clinical disease. To create a model of antiestrogen responsive BC with spontaneous metastasis, we developed a mouse model of 4T1.2 triple-negative (TN) breast cancer with virally transduced ER expression that metastasizes spontaneously without exogenous estrogen stimulation and is responsive to antiestrogen drugs. Our mouse model exhibited upregulated ER-responsive genes and multi-organ metastasis without exogenous estrogen administration. Additionally, we developed a second TN BC cell line, E0771/bone, to express ER, and while it expressed ER-responsive genes, it lacked spontaneous metastasis to clinically important tissues. Following antiestrogen treatment (tamoxifen, ICI 182,780, or vehicle control), 4T1.2- and E0771/bone-derived tumor volumes and weights were significantly decreased, exemplifying antiestrogen responsivity in both cell lines. This 4T1.2 tumor model, which expresses the estrogen receptor, metastasizes spontaneously, and responds to antiestrogen treatment, will allow for further investigation into the biology and potential treatment of metastasis.

Tolerability and effectiveness of fulvestrant as first-line endocrine therapy in unselected patients with advanced breast cancer (ABC): Results of a multicenter, single arm, non-interventional study.

e13061 Background: Fulvestrant, a selective estrogen receptor (ER) down-regulator, is a standard of care for first-line treatment in hormone receptor-positive (HR+) advanced breast cancer. This study is to assess the safety profile and effectiveness of fulvestrant 500mg as the first-line endocrine therapy of post-menopausal women with HR+ locally advanced or metastatic breast cancer. Methods: The study is an open-label, multicentre, prospective, observational study in China. Chinese patients receiving fulvestrant 500mg as the first endocrine agent after relapse according to investigator’s clinical practice were enrolled. Primary variable is the frequency and severity of adverse events (AEs). Secondary variables were objective response rate (ORR), clinical benefit rate (CBR), progress free survival (PFS) and overall survival (OS). Predictive effects of endocrine resistance, chemotherapy for advanced disease and adjuvant endocrine therapy on the effectiveness were prespecified as exploratory variables. Results: From November 2017 to December 2020, 461 patients were enrolled by 29 Chinese centers. Median age was 56 years and the ECOG score was: 0, 165 (35.8%); 1, 281 (60.9%); 2, 12 (2.6%); and 3, 3 (0.7%). 20 (4.3%) patients had the Kaplan-Feinstein index ≥2. Majority (77.0%) of the patients were ER+ and PgR+, and 190 (41.2%) had visceral metastasis. In total, 91 (19.7%) patients were primary endocrine resistant, 202 (43.8%) were secondary endocrine resistant and 123 (26.7%) were endocrine-therapy naïve. 147 (31.9%) patients received previous chemotherapy for advanced disease, while 101 (21.9%) patients had anti-estrogen drugs as adjuvant therapy. 54 (11.7%) patients had concurrent CDK4/6 inhibitors. After a median follow-up of 26.8 months (IQR 18.7-38.2), median PFS was 13.0 months (95% CI 9.8-16.4) and median OS was 41.2 months (95% CI 37.3-NE). ORR was 11.3% (95% CI 8.2-15.1) and CBR was 60.6% (95%CI 55.2-65.8). Patients with endocrine-therapy naïve tumor, no previous chemotherapy for advanced disease and adjuvant anti-estrogen treatment had a longer PFS of first-line fulvestrant 500mg. 67 (14.5%) patients had at least one AE, with 1 (0.2%) patient withdrawing because of AEs. Drug-related serious AEs (SAEs) were rare, occurring in 2 (0.4%) patients. No patient died as a result of a drug-related AE. Neutropenia, increased ALT/AST, and anemia were the most commonly reported AEs in this study. Conclusions: This is the first prospective real-world study confirming that fulvestrant 500mg is a well-tolerated treatment option in unselected ABC in China. In the real clinical practice, fulvestrant 500mg can achieve the consistent anti-tumor activity as in clinical trials. Patients with endocrine-therapy naïve status and no prior chemotherapy tend to have a longer control time. Clinical trial information: NCT02909361 .

Pulmonary benign metastasizing leiomyoma in patients aged 45 years and younger: clinical features and novelty in treatment

BackgroundPulmonary benign metastasizing leiomyoma (PBML) is the most common extrauterine spread of uterine leiomyoma, and its biological behavior is traditionally thought to be hormone dependent. Studies on older PBML patients have been previously reported, but limited literature has been published regarding the clinical features and treatment of PBML in young women.MethodsA total of 65 cases of PBML in women aged 45 years and younger were reviewed, including 56 cases selected from PubMed and 9 cases from our hospital. The clinical characteristics and management of these patients were analyzed.ResultsThe median age of all the patients at diagnosis was 39.0 years. PBML most commonly presented as bilateral solid lesions (60.9%), with other rare imaging manifestations. The median interval time from a pertinent gynecologic procedure to diagnosis was 6.0 years. A total of 16.7% of patients received careful observation, and all achieved stable status in a median follow-up time of 18.0 months. A total of 71.4% of patients were administered anti-estrogen therapies, including surgical castration (33.3%), gonadotropin-releasing hormone analog (23.8%) and anti-estrogen drugs (14.3%). Eight of 42 patients underwent surgical resection of metastatic lesions. Patients who underwent curative surgery for the removal of pulmonary lesions combined with adjuvant anti-estrogen therapies had favorable outcomes compared with those who only underwent surgical resection. The disease control rates of surgical castration, gonadotropin-releasing hormone analog, and anti-estrogen drugs were 85.7%, 90.0%, and 50.0%, respectively. For two patients, sirolimus (rapamycin) achieved successful relief of symptoms and control of pulmonary lesions without lowering hormone levels and causing estrogen deficiency symptoms.ConclusionsIn the absence of standard treatment guidelines for PBML, maintaining a low-estrogen environment using different kinds of antiestrogen therapies has been the mainstream strategy and has satisfying curative effects. A wait-and-see strategy might be an option, but therapeutic approaches must be contemplated when complications or symptoms progress. For PBML in young women, the negative effect on ovarian function of anti-estrogen treatment, especially surgical castration, should be considered. Sirolimus might be a new treatment option for young PBML patients, especially for those who want to preserve ovarian function.

Research Progress of Mono- antibody Therapy for Breast Cancer

Breast cancer is the most prevalent form of cancer and the second greatest cause of death from cancer among female population. Traditional medication of breast cancer usually indicates anti-estrogen drugs and aromatase inhibitors. Monoclonal antibodies (mAbs) are a type of advancing immunotherapy that has become commonly used to treat cancers since it uses antibodies to target and destroy malignant cells specifically. Among them, trastuzumab is a humanized mAb derived from recombinant DNA. It can specifically react to the extracellular part of human epidermal growth factor receptor-2 (HER-2). Research proved inhibitory effect of trastuzumab on the proliferation of certain tumor cell, and is also a potential material for antibody dependent cell-mediated cytotoxic reaction. While there are a variety of forms in the disease, and each form has a unique assortment of surface antigens, making it difficult to treat with a single type of mAb. Therefore, further work is needed to develop monoclonal-based antibodies that can target multiple forms of breast-related cancer. Furthermore, researches trying to create mAbs that can be combined with conventional cancer therapies like radiotherapy and chemotherapy are still being done. Here we summarized recent researches on mAb therapy for breast cancer and discusses the challenges as well as the progresses in this area.

An Update on Tamoxifen and the Chemo-Preventive Potential of Vitamin E in Breast Cancer Management.

Breast cancer (BC) is the most common female cancer in terms of incidence and mortality worldwide. Tamoxifen (Nolvadex) is a widely prescribed, oral anti-estrogen drug for the hormonal treatment of estrogen-receptor-positive BC, which represents 70% of all BC subtypes. This review assesses the current knowledge on the molecular pharmacology of tamoxifen in terms of its anticancer and chemo-preventive actions. Due to the importance of vitamin E compounds, which are widely taken as a supplementary dietary component, the review focuses only on the potential importance of vitamin E in BC chemo-prevention. The chemo-preventive and onco-protective effects of tamoxifen combined with the potential effects of vitamin E can alter the anticancer actions of tamoxifen. Therefore, methods involving an individually designed, nutritional intervention for patients with BC warrant further consideration. These data are of great importance for tamoxifen chemo-prevention strategies in future epidemiological studies.

Bone Marrow Mesenchymal Stem Cells Induce Metabolic Plasticity in Estrogen Receptor-Positive Breast Cancer.

This study reveals how MSCs reprogram metabolism of ER+ breast cancer cells and point to MCT4 as potential therapeutic target to overcome resistance to antiestrogen drugs.

Abstract IA017: Targeting the mTOR pathway for the prevention of triple-negative breast cancer

Abstract Phase III cancer prevention clinical trials have shown that breast cancer prevention is feasible using anti-estrogen drugs. However, these drugs have not been widely accepted because of concerns about toxicity. In addition, anti-estrogen drugs do not prevent estrogen-negative breast cancers, including the most aggressive form of breast cancer, triple-negative breast cancer (TNBC), that does not express the estrogen receptor (ER), progesterone receptor, or the human epidermal growth factor receptor 2 (HER2). Our laboratory is focused on identifying growth-regulatory molecules that are essential for the growth of TNBCs. For this study, we identified mTOR as an essential growth-regulatory molecule that is highly expressed in TNBCs. We then investigated whether the mTOR inhibitor everolimus can prevent mammary tumors in transgenic mouse models including 4 models of TNBC and one model of ER-negative/HER2-positive breast cancer. Everolimus treatment significantly delayed mammary tumor formation but with a varying degree in all five mouse models. Everolimus treatment for up to 1 year was well tolerated with no observable toxicity. These results suggest that mTOR inhibitors may be promising drugs for the prevention of ER-negative and triple-negative breast cancers in women at risk of these aggressive breast cancers. Grant support: This research was supported by an NCI-PREVENT contract to P. Brown and A. Mazumdar (HHSN261201500018I/HHSN26100006). Citation Format: Powel H. Brown, Abhijit Mazumdar, William Tahaney, Jamal Hill, Yun Zhang, Sumankalai Ramachandran, Jitesh Kawedia, Jing Qian, Alejandra Contreras, Michelle Savage, Lana Vornik. Targeting the mTOR pathway for the prevention of triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr IA017.

Expression patterns and clinical significance of estrogen receptor in non-small cell lung cancer.

Lung cancer death remains the highest among all malignancies. Gender differences show women have an increased cancer incidence while men have worse outcomes. These observations identified that some lung carcinomas express estrogen receptors (ER). This is a promising target as antiestrogen drugs can reduce tumors and improve survival. However, there is a limited understanding of ER distribution and its clinical significance to properly design antiestrogen drug clinical trials. Thus, we comprehensively analyzed ERα and ERβ expression patterns by gender, cancer cell type, and receptor location in lung cancer. We conducted a systematic review using the PubMed database from all-time through October 2022, using MeSH terms with the keywords "lung cancer," "estrogen receptor," and "immunohistochemistry." We identified 120 studies with 21 reports being evaluated based on our inclusion criteria. We examined 4874 lung cancers from 5011 patients. ERβ is the predominant form of ER expressed, mainly found in the nucleus. The ERβ positivity rate is 51.5% in males versus 55.5% in females and was not statistically different. In contrast, ERα is predominately extranuclear in location, and ERα expression varies by gender. Males had a positivity rate of 31% versus 26.6% in females, which is statistically different. ERα is associated with a worse prognosis in some studies, while it had no effect in others. Overall, ERβ was associated with a better prognosis. We characterized ER expression patterns in 4874 lung cancers. Over 50% expressed ERβ with equal rates in both sexes and was associated with a better prognosis. ERα expression was slightly higher in males (31%) than females (26.6%) and was associated with a poor prognosis. Our findings suggest estrogen signaling may be a promising drug target in lung cancer.

Mechanisms of Endocrine Resistance in Hormone Receptor-Positive Breast Cancer.

Hormone receptor-positive (HR+) breast cancer (BC) accounts for approximately 70% of all breast invasive tumors. Endocrine therapy (ET) represents the standard treatment for HR + BC. Most patients, however, eventually develop resistance to ET, which limits their effectiveness and poses a major challenge for the management of HR + BC. Several mechanisms that contribute to ET resistance have been described. One of the most common mechanisms is the upregulation of alternative signaling pathways that can bypass estrogen dependency, such as activation of the PI3K/Akt/mTOR as well as mitogen-activated protein kinase (MAPK) and the insulin-like growth factor 1 receptor (IGF-1R) pathways. Another common mechanism of endocrine resistance is the acquisition of activating mutations of ESR1, which encodes for the estrogen receptor, that lead to structural changes of the receptor, prevent the binding to anti-estrogen drugs and result in constitutive activation of the receptor, even in the absence of estrogens. Epigenetic changes, such as DNA methylation and histone modifications, can also contribute to ET resistance by altering the expression of genes that are involved in estrogen signaling. Understanding the mechanisms of resistance to ET is crucial for the development of new therapies that can overcome resistance and improve outcomes for patients with HR + BC.

Prolonged Disease-Free Survival in a Relapsed Adult Granulosa Cell Tumor of the Ovary Treated by Combined Leuprolide and Letrozole: Case Report

Relapsing ovarian granulosa-cell tumor (GCT) is a challenge for physicians due to the lack of effective therapy. Current strategies did not improve the 80% death rate of recurrent disease. GCTs synthesize estrogens and express follicle-stimulating hormone, gonadotropin-releasing hormone, and estrogen and progesterone receptors. The FOXL2-C134W mutation is shared in all GCTs, and its downregulation of hormone-related apoptosis appears causal in induction of tumor phenotype. On these assumptions, hormone anti-estrogenic therapies have been proposed for recurrent GCTs. A 32-year-old woman suffering from GCT was first treated by surgery in 2004 and staged as IA disease. Two subsequent pelvic relapses were diagnosed in 2006 and 2007, and the patient underwent surgery and chemotherapy to treat both recurrences. Overall, she underwent five subsequent surgical interventions and two chemotherapy instances. A third single pelvic relapse above the vaginal cuff was diagnosed in 2013. Based on the patient’s refusal to undergo further surgery we proposed an anti-estrogen therapy consisting of combined GnRH analogue leuprolide and the aromatase inhibitor letrozole. Complete remission was obtained after 3 months from the start of therapy. Subsequently, we found that disease-free survival was maintained over 9 years of treatment. Although recent reports indicate poor effectiveness of hormone therapy to treat recurrent GCTs, the success of this case indicates that a subset of patients with recurrent GCT maintain a tumor phenotype highly responsive to anti-estrogen drugs.

Molecular Mechanisms of Anti-Estrogen Therapy Resistance and Novel Targeted Therapies.

Breast cancer (BC) is the most commonly diagnosed cancer in women, constituting one-third of all cancers in women, and it is the second leading cause of cancer-related deaths in the United States. Anti-estrogen therapies, such as selective estrogen receptor modulators, significantly improve survival in estrogen receptor-positive (ER+) BC patients, which represents about 70% of cases. However, about 60% of patients inevitably experience intrinsic or acquired resistance to anti-estrogen therapies, representing a major clinical problem that leads to relapse, metastasis, and patient deaths. The resistance mechanisms involve mutations of the direct targets of anti-estrogen therapies, compensatory survival pathways, as well as alterations in the expression of non-coding RNAs (e.g., microRNA) that regulate the activity of survival and signaling pathways. Although cyclin-dependent kinase 4/6 and phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors have significantly improved survival, the efficacy of these therapies alone and in combination with anti-estrogen therapy for advanced ER+ BC, are not curative in advanced and metastatic disease. Therefore, understanding the molecular mechanisms causing treatment resistance is critical for developing highly effective therapies and improving patient survival. This review focuses on the key mechanisms that contribute to anti-estrogen therapy resistance and potential new treatment strategies alone and in combination with anti-estrogen drugs to improve the survival of BC patients.

74 Hereditary angioedema revealed by compartment syndrome

BackgroundHereditary angioedema (HAE) can present with a wide spectrum of clinical symptoms, including articular features like the compartment syndrome.ObjectiveWe present the peculiar case of a young female patient suffering from this rare complement system disorder and presenting as a « wrist oedema ».MethodsA 14-year-old girl was admitted in the emergency room during a night shift. She presented with acute compartment (wrist) syndrome due to edematous compression of the median nerve, associated with a typical personal history of HAE. It resolved within 6 h with IV steroids and hyperhydration.The quantitative and qualitative C1 INH esterase returning negative, the diagnosis of HAE type III was made.The patient was treated with long-term treatment based on Danazol, (the most frequently prescribed attenuated androgen to treat HAE).ResultsHAE is due to the deficiency or dysfunction of the C1 inhibitor protein (quantitative or qualitative deficiency). A new nomenclature has replaced the initial use of denominations HAE type 1, 2 or 3; to speak rather of HAE with a deficient C1 inhibitor (type 1), with a dysfunctional C1 inhibitor (type 2) or with a normal C1 inhibitor (type 3)Type 3 HAE is rare and difficult to treat. It may respond to anti-estrogenic drugs such as progestins and especially to androgens; specific (very expensive) molecules do exist and act directly on the bradykinin pathwaysConclusionA compartment syndrome may reveal extremely rare conditions such as hereditary angioedema.Early recognition and management are the guarantee of a preserved functional prognosis.

Targeting the mTOR Pathway for the Prevention of ER-Negative Breast Cancer.

Our results show that everolimus delays mammary tumor formation in multiple mouse models, suggesting that mTOR inhibitors will be useful for the prevention of ER-negative and triple-negative breast cancer in humans. See related Spotlight, p. 787.