MF101: a multi-component botanical selective estrogen receptor beta modulator for the treatment of menopausal vasomotor symptoms

INTRODUCTION: The Women's Health Initiative Estrogen Plus Progestin clinical trial demonstrated the risks exceeded the benefits which have led to a decline in menopausal hormone therapy (MHT) by greater than 50%. MHT use was initiated long before there was a significant understanding of the molecular mechanisms of estrogens. It has become clear that the problem with the current estrogens in MHT is they act non-selectively as an agonist in all tissues that contain estrogen receptors. MF101 is an oral, botanically derived extract that was designed to selectively regulate estrogen receptor beta (ERβ) because the increased risk of breast and endometrial cancer is due to the activation of estrogen receptor alpha (ERα) by estrogens. Preclinical and clinical data support a role for selective ERβ agonists, such as MF101, for vasomotor symptoms without increasing cancer risks. AREAS COVERED: The review covers the biological, pharmacological and clinical advantages of MF101, and the unique ability of MF101 to selectively target the ERβ pathway for the treatment of hot flashes (HF). EXPERT OPINION: Preclinical and clinical studies indicate that MF101, a selective estrogen receptor beta agonist, represents a new class of drugs that is safe and effective for treating HF and nighttime awakenings.     

氟维司群治疗乳腺癌的若干问题

氟维司群是一种新型甾体雌激素受体拮抗药,可在细胞水平下调雌激素受体和孕激素受体数量,且无激动效应。氟维司群对激素受体阳性的乳腺癌疗效确切,耐受性好,是一种新的内分泌治疗药物。本文回顾氟维司群治疗乳腺癌的临床研究进展,讨论若干临床应用关键问题。     

The role of estrogen receptor in melanoma

The estrogen receptor (ER) belongs to the group of sex hormone receptors and binds the biologically active form of estrogen, 17β-estradiol. Expression of ER in tumor tissue is a well-established prognostic marker in breast cancer. The role of ER has been extensively studied in several other types of human cancers. This report investigates the potential role of ER as a surrogate marker for predicting melanoma progression, response to therapy, and patient survival. In addition, the authors review what is known, so far, about ER signaling pathways and their potential role in carcinogenesis and progression of cutaneous melanoma. Possibilities and limitations of using ER as a therapeutic target in the treatment of melanoma is also discussed.     

The role of estrogen receptor in melanoma

The estrogen receptor (ER) belongs to the group of sex hormone receptors and binds the biologically active form of estrogen, 17beta-estradiol. Expression of ER in tumor tissue is a well-established prognostic marker in breast cancer. The role of ER has been extensively studied in several other types of human cancers. This report investigates the potential role of ER as a surrogate marker for predicting melanoma progression, response to therapy, and patient survival. In addition, the authors review what is known, so far, about ER signaling pathways and their potential role in carcinogenesis and progression of cutaneous melanoma. Possibilities and limitations of using ER as a therapeutic target in the treatment of melanoma is also discussed.     

A-CD estrogens. I. Substituent effects, hormone potency, and receptor subtype selectivity in a new family of flexible estrogenic compounds

Long-term use of estrogen supplements by women leads to an increased risk of breast and uterine cancers. Possible mechanisms include metabolism of estradiol and compounds related to tumor-initiating quinones, and ligand-induced activation of the estrogen receptors ERα and ERβ which can cause cancer cell proliferation, depending on the ratio of receptors present. One therapeutic goal would be to create a spectrum of compounds of variable potency for ERα and ERβ, which are resistant to quinone formation, and to determine an optimum point in this spectrum. We describe the synthesis, modeling, binding affinities, hormone potency, and a measure of quinone formation for a new family of A-CD estrogens, where the A-C bond is formed by ring coupling. Some substituents on the A-ring increase hormone potency, and one compound is much less quinone-forming than estradiol. These compounds span a wide range of receptor subtype selectivities and may be useful in hormone replacement therapy.     

Nuclear hormone receptor signals as new therapeutic targets for urothelial carcinoma

Unlike prostate and breast cancers, urothelial carcinoma of the urinary bladder is not yet considered as an endocrine-related neoplasm, and hormonal therapy for bladder cancer remains experimental. Nonetheless, there is increasing evidence indicating that nuclear hormone receptor signals are implicated in the development and progression of bladder cancer. Androgen-mediated androgen receptor (AR) signals have been convincingly shown to induce bladder tumorigenesis. Androgens also promote the growth of AR-positive bladder cancer cells, although it is controversial whether AR plays a dominant role in bladder cancer progression. Both stimulatory and inhibitory functions of estrogen receptor signals in bladder cancer have been reported. Various studies have also demonstrated the involvement of other nuclear receptors, including progesterone receptor, glucocorticoid receptor, vitamin D receptor, and retinoid receptors, as well as some orphan receptors, in bladder cancer. This review summarizes and discusses available data suggesting the modulation of bladder carcinogenesis and cancer progression via nuclear hormone receptor signaling pathways. These pathways have the potential to be an extremely important area of bladder cancer research, leading to the development of effective chemopreventive/therapeutic approaches, using hormonal manipulation. Considerable uncertainty remains regarding the selection of patients who are likely to benefit from hormonal therapy and optimal options for the treatment.     

Estrogen receptor beta in cancer: an attractive target for therapy

While it is well documented that the mitogenic actions of estrogens are critical in the development and progression of human breast and some gynecologic cancers, only latest data demonstrate a crucial involvement of estrogen-signaling in the carcinogenesis of non-classical estrogen target tissues, as colon, prostate, lung, skin, and brain. Only recently it has also been found out that the biological effects of estrogens are mediated by two distinct estrogen receptors (ERs), ERα and ERβ, and that their relative levels in a given cell are important determinants of response to estradiol and selective estrogen receptor modulators. Indeed, although ERα and ERβ have similar structure, they produce different effects, and there is currently increasing evidence that, for some tumors, an imbalanced ERβ expression might play a pivotal role in tumor development and progression. However, the prognostic value, the potential significance in predicting response to endocrine therapy, and, eventually, the utility of ERβ as a therapeutic target need to be assessed in large-scale and prospective clinical studies. This review examines the experimental and clinical evidences for a role of ERβ in carcinogenesis of classical and nonclassical estrogen target tissues. If anomalies of ERβ expression could be demonstrated to represent a critical step in the development and progression of some types of cancers, its re-expression by genetic engineering, as well as the use of targeted ERβ therapies would constitute new important therapeutic approaches.     

淫羊藿提取物对绝经后骨质疏松、乳腺癌和前列腺癌的标准化、临床前和临床评价（英文）

Estrogens are critical for bone health and the development of breast and prostate tissues.At menopause,our cohort studies show that naturally occurring estrogens in the body protect against osteoporotic hip fractures,but can also increase the risk of breast cancer.Extracts of Epimediumspp.is widely used to treat osteoporosis and improve general health in post-menopausal women.Prenylated flavonoids from Epimedium spp.exert potent estrogenic effects making it an attractive alternative to estrogen replacement therapy for treatment of osteoporosis.Lead compounds from epimedium such as icaritin impact pro-osteoblastic,anti-osteoclastic signaling pathways in bone cells;and anti-tumour effect on nuclear receptors in breast and prostate cancer animal models.Oral administration of a Epimedium spp.extract in openlabel,two-period,randomized,crossover study indicate significant ex-vivo effects on ERαand ERβ-mediated bioactivities and breast cancer cell proliferation.Challenges in the taxonomy,standardization and quality manufacturing of extracts suitable for pharmacokinetic,pharmacodynamics and efficacy studies in humans will be discussed.     

乳腺癌原发灶与转移灶内雌激素受体及孕激素受体水平变化分析

目的 分析乳腺癌原发灶与转移灶内雌激素受体(ER)及孕激素受体(PR)水平变化的临床意义.方法 82例存在远处转移灶或腋窝淋巴结转移灶的乳腺癌患者,其中远端转移灶患者40例,腋窝淋巴结转移灶患者42例.切除患者局部组织,获取乳腺癌原发灶及转移灶组织,采用免疫组织化学(免疫组化)方法检测病灶中ER、PR水平.分析比较原发...     

Estrogens and colorectal cancer

In recent years, several lines of epidemiologic, clinical and experimental evidences have been reported showing that estrogen hormones may be involved in malignant colorectal tumors. The sex differences in site-specific incidence, the increased incidence of colonic cancer in women with breast cancer, the protective effect of increasing parity and the reduced risk among women taking postmenopausal hormones, are all elements suggesting that sex hormones may play a role. Male rats experimentally exposed to the carcinogen dimethylhydrazine, have twice the risk of developing colon cancer and significantly shorter survival times than their female counterparts. Along with the clinical, experimental and epidemiologic findings there are also biologic reasons why estrogen may be protective. Most estrogen action appears to be exerted via the estrogen receptors (ERs) on target cells. ERs have been reported in several solid tumors including gastrointestinal neoplasms such as esophageal, gallbladder, gastric and colorectal cancer. At the end of 1995, a second ER (ER-beta) was cloned from the rat prostate cDNA library and subsequently, the human and mouse homologs. Its demonstration in normal and neoplastic human colorectal tissues and "in vitro" in colonic epithelial cells, has renewed interest in investigating the existence of two ER subtypes. The presence of two ERs could explain the selective actions of estrogens on different target tissues and, particularly, on the gastrointestinal tract. Finally, our studies suggest that estrogens and their receptors play an important role in the growth and progression of colorectal tumors, by interacting with other molecules required for cell proliferation like growth factors and polyamines.     

Molecular basis of therapeutic strategies for breast cancer

The development of breast cancer is the consequence of uncontrolled growth and division of breast-ductal epithelial cells. While many factors contribute to its etiology, estrogen hormones within the context of many interrelated growth signaling pathways play critical roles for the initiation and development of breast cancer. The effects of estrogens are primarily mediated by the estrogen receptors (ERs) alpha and beta. ER mediates a complex array of genomic and non-genomic events that orchestrate cellular metabolism, mitogenesis, morphogenesis, motogenesis, and apoptosis. The current modalities for the treatment of breast cancer have centered on the development of agents with diverse pharmacology to reduce/ablate the circulating estrogens or to alter/prevent ER function. Approaches to perturb the estrogen environment are successful usually in the remission of established tumors. However, many breast tumors are not responsive or eventually develop resistance to endocrine therapies. Despite considerable effort, the mechanism for the non-responsiveness and acquisition of resistance remains unclear. The establishment of hormone responsiveness is one of the current approaches for the development of an effective therapeutic modality for de novo resistant breast tumors. Re-establishment of loss of ER synthesis/function, on the other hand, constitutes a primary therapeutic goal for acquired resistance neoplasms. We have recently engineered transregulatory proteins that specifically targeted and robustly regulated estrogen responsive genes independent of ligand, ER-subtype and cell-context. The targeted regulation of estrogen responsive gene networks by these designer transregulators could provide a basis for the development of novel approaches for experimental biology and medicine.     

Nuclear imaging of hormonal receptor status in breast cancer: a tool for guiding endocrine treatment and drug development

Breast cancer is a commonly occurring disease in women and a major cause of morbidity and mortality. In the past decades, the development of medical endocrine therapies has led to a significant improvement in treatment outcome for this type of cancer. This therapy is targeting specific hormone receptors that are overexpressed by the tumor cells. In breast cancer, estrogen and progesterone receptors are important targets and therefore the receptor status of the tumor strongly determines treatment outcome. However, the receptor status can change during the course of the disease and consequently therapy resistance can occur. Therefore, insight in the current receptor status of the tumor is essential for optimal treatment. Nuclear imaging techniques like positron emission tomography (PET) and single photon emission computed tomography (SPECT), could provide the means to monitor the receptor status of tumors and the receptor occupancy by medical endocrine drugs in a non-invasive manner. Thus, these imaging techniques could offer a tool to guide therapy management in the individual patient. Nuclear imaging techniques for some of the relevant receptors for treatment of breast cancer are currently available. These imaging techniques could also aid the development of novel treatment strategies like modulation of hormone receptor expression. This review will address the role of hormone receptors in breast cancer treatment, the available nuclear imaging methods for monitoring the receptor status, the potential role of nuclear imaging in therapy management and drug development.     

Selectively targeting estrogen receptors for cancer treatment

Estrogens regulate growth and development through the action of two distinct estrogen receptors (ERs), ERα and ERβ, which mediate proliferation and differentiation of cells. For decades, ERα mediated estrogen signaling has been therapeutically targeted to treat breast cancer, most notably with the selective estrogen receptor modulator (SERM) tamoxifen. Selectively targeting ERs occurs at two levels: tissue selectivity and receptor subtype selectivity. SERMs have been developed with emphasis on tissue selectivity to target ER signaling for breast cancer treatment. Additionally, new approaches to selectively target the action of ERα going beyond ligand-dependent activity are under current investigation. As evidence of the anti-proliferative role of ERβ accumulates, selectively targeting ERβ is an attractive approach for designing new cancer therapies with the emphasis shifted to designing ligands with subtype selectivity. This review will present the mechanistic and structural features of ERs that determine tissue and subtype selectivity with an emphasis on current approaches to selectively target ERα and ERβ for cancer treatment.     

Two novel GPER agonists induce gene expression changes and growth effects in cancer cells

Although the action of estrogens has been traditionally explained by the binding to and transactivation of the nuclear estrogen receptor (ER)α and ERβ, recently the G protein-coupled receptor GPR30/GPER has been involved in the rapid estrogen signaling. We investigated the ability of two original molecules, which were named GPER-L1 and GPERL2, to bind to and activate the GPER transduction pathway in cancer cells. Competition assays, docking simulations, transfection experiments, real-time PCR, immunoblotting, gene silencing technology and growth assays were performed to ascertain the selective action of GPER-L1 and GPER-L2 in activating the GPER-mediated signaling. Both compounds, which did not show any ability to bind to and activate the classical ERs, were able to bind to GPER and to trigger the rapid activation of the GPER/EGFR/ERK transduction pathway which led to the up-regulation of GPER-target genes. Notably, GPER-L1 and GPER-L2 induced the proliferation of SkBr3 breast and Ishikawa endometrial cancer cells at nM concentrations through GPER, hence providing further evidence on their capability to elicit relevant biological responses mediated by GPER. The identification and characterization of these novel compounds as selective GPER agonists represent a valuable tool to further dissect the pharmacology of this novel estrogen receptor and to better differentiate the specific functions elicited by each estrogen receptor subtype in cancer cells.     

PET imaging of steroid receptor expression in breast and prostate cancer

The vast majority of breast and prostate cancers express specific receptors for steroid hormones, which play a pivotal role in tumor progression. Because of the efficacy of endocrine therapy combined with its relatively mild side-effects, this intervention has nowadays become the treatment of choice for patients with advanced breast and prostate cancer, provided that their tumors express hormone receptors. However, in case of breast cancer it is well known that part of the patients have hormone receptor-negative tumors at diagnosis, whereas other patients have discordant receptor expression across lesions. In addition, receptor expression can change during therapy and result in resistance to this therapy. Besides several lines of hormonal treatments, also other strategies to affect the hormone receptors are currently under investigation, namely histone deacetylases (HDAC) and heat shock protein (HSP) inhibitors. Knowledge of the actual receptor status can support optimal treatment decision-making and the evaluation of new drugs. Positron emission tomography (PET) is a non-invasive nuclear imaging technique that allows monitoring and quantification of hormone receptor expression across lesions throughout the body. Several PET tracers have been developed for imaging of the most relevant hormone receptors in breast and prostate cancer: i.e. the estrogen, progesterone and androgen receptors. Some of these PET tracers have been successfully applied in early clinical studies. This review will give an overview of the current status of PET imaging of hormone receptors in breast and prostate cancer.