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It is very important to examine the influence of inhibition of in situ estrogen production on the pathobiology of human sex steroid-dependent tumors in order to understand the clinical effects of aromatase inhibitors. We have examined the biological changes before and after aromatase inhibitor treatment in vitro (endometrial and ovarian cancer) and in vivo (breast cancer). First, we analyzed these changes using histoculture of 15 human endometrial cancers and 9 ovarian cancers. Five of the fifteen endometrial cancers and four of the nine ovarian cancers demonstrated decreased [3H]thymidine uptake or Ki67 labeling index after 14alpha-hydroxy-4-androstene-3,6,17-trione (NKS01) treatment. In ovarian cancer cases, the responsive cases tended to be associated with higher aromatase and estrogen receptor alpha (ER) expression compared with the other cases but this was not seen in the endometrial cancer cases. There were no changes in ER and aromatase expression before and after NKS01 treatment in either ovarian or endometrial cancer cases. We then studied the same primary human breast tumors before and after aminoglutethimide (AMG, n=3) and 4-hydroxyandrostenedione (4-OHA, n=3) treatment. Tumor aromatase activity increased in 3 cases and decreased or was unchanged in 3 cases but aromatase immunoreactivity in stroma and adipocytes was unaltered in 5 cases. There were no changes in the ER labeling index before or after treatment. Five of the six cases including the responsive cases tended to be associated with decreased cell proliferation or Ki67 expression and increased apoptosis when examined by the TUNEL method. These results indicate that aromatase inhibitors may exert their effects on human breast and other cancers through decreasing proliferation and increasing apoptosis, possibly without altering ER status.
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Oral contraceptive (OC) use significantly reduces the risk of endometrial and ovarian cancer, has only a minimal effect on breast cancer, but may increase the risk of cervical cancer. These effects can be readily explained in terms of the effects of OCs on cell proliferation in these tissues. This analysis suggests how a hormonal contraceptive based on a GnRH agonist plus low-dose add-back sex steroids could be made that would greatly reduce lifetime risk of breast and ovarian cancer. Such a hormonal contraceptive is also likely to significantly reduce the lifetime risk of cervical cancer. It is also likely to reduce the risk of endometrial cancer, although not to the same extent as OCs.
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Approximately 80% of human ovarian and endometrial cancers and 50% of breast cancers express GnRH and its receptor as part of an autocrine regulatory system. After binding of its ligand the tumor GnRH receptor couples to G-protein alphai and activates a variety of intracellular signaling mechanisms. (1) Through activation of a protein tyrosine phosphatase, autophosphorylation of growth factor receptors is reverted leading to an inhibition of mitogenic signaling and reduced cell proliferation. (2) Through activation of nuclear factor kappa B antiapoptotic mechanisms are induced protecting tumor cells from apoptosis induced, for example, by doxorubicin. (3) Through activation of the Jun kinase pathway AP-1 is induced, leading to cell cycle arrest in the G0/G1 phase. It seems reasonable to speculate that this system enables the tumor cell to reduce proliferation and to activate repair mechanisms while being protected simultaneously from apoptosis. Interestingly, GnRH antagonists show the same activity in this system as agonists, indicating that the dichotomy GnRH agonist-GnRH antagonist defined in the pituitary gonadotrope is not valid for the tumor GnRH system. Recently, a second type of GnRH receptor, specific for GnRH-II, has been identified in ovarian and endometrial cancers, which transmits significantly stronger antiproliferative effects than the GnRH-I receptor. GnRH antagonists have agonistic effects on this type II receptor. In animal models of human cancers, GnRH antagonists had stronger antitumor effects than GnRH agonists. Therefore, we performed a phase II clinical trial with the GnRH antagonist, cetrorelix (10 mg/day), in patients with ovarian or mullerian carcinoma refractory to platinum chemotherapy. Of 17 evaluable patients treated with cetrorelix, 3 obtained a partial remission (18%) which lasted for 2 to 6 months. Furthermore, 6 patients experienced disease stabilization (35%) for up to 1 year. In this very refractory patient population (median number of prior chemotherapies = 3) these results are quite remarkable when compared with palliative chemotherapy. In addition, cytotoxic GnRH analogs have been developed, where for example doxorubicin was covalently coupled to GnRH analogs. These compounds have superior antitumor effects in cancers expressing GnRH receptors as compared with native doxorubicin and allow for a targeted cytotoxic chemotherapy of gynecologic and breast cancers.
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The idea of breast cancer prevention by hormonal means stemmed from the results of treatment trials, many of them carried out by the National Surgical Adjuvant Breast and Bowel Project (NSABP). Over the years, a number of NSABP treatment studies demonstrated that breast cancer recurrence was reduced in women with the disease who were given tamoxifen, a selective estrogen receptor (ER) modulator (SERM). Five subsequent tamoxifen prevention trials with this agent have shown a 48% reduction in ER-positive cancers, but no effect for ER-negative cancers, and an increase in endometrial cancer and thromboembolic events. The drug raloxifene, another SERM, originally examined as an osteoporosis agent, has also shown promise for the prevention of breast cancer, although, as with tamoxifen, the drug carries a risk for thromboembolic events. There is recent evidence in a large treatment trial that the aromastase inhibitor anastrazole, a 'pure anti-estrogen', holds promise as a breast cancer preventive agent. Longer follow-up and the testing of additional agents is required before these drugs can be used widely for prevention. In addition, future research should focus on the identification of at-risk women who can perhaps be targeted for specific prevention agents.
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In the context of multiple neuroendocrine tumor syndromes, reproductive abnormalities may occur via a number of different mechanisms, such as hyperprolactinemia, increased GH/IGF-1 levels, hypogonadotropic hypogonadism, hypercortisolism, hyperandrogenism, hyperthyroidism, gonadotropin hypersecretion, as well as, tumorigenesis or functional disturbances in gonads or other reproductive organs. Precocious puberty and/or male feminization is a feature of McCune–Albright syndrome (MAS), neurofibromatosis type 1 (NF1), Carney complex (CNC), and Peutz–Jeghers syndrome (PJS), while sperm maturation and ovulation defects have been described in MAS and CNC. Although tumorigenesis of reproductive organs due to a multiple neuroendocrine tumor syndrome is very rare, certain lesions are characteristic and very unusual in the general population. Awareness leading to their recognition is important especially when other endocrine abnormalities coexist, as occasionally they may even be the first manifestation of a syndrome. Lesions such as certain types of ovarian cysts (MAS, CNC), pseudogynecomastia due to neurofibromas of the nipple–areola area (NF1), breast disease (CNC and Cowden disease (CD)), cysts and ‘hypernephroid’ tumors of the epididymis or bilateral papillary cystadenomas (mesosalpinx cysts) and endometrioid cystadenomas of the broad ligament (von Hippel–Lindau disease), testicular Sertoli calcifying tumors (CNC, PJS) monolateral or bilateral macroochidism and microlithiasis (MAS) may offer diagnostic clues. In addition, multiple neuroendocrine tumor syndromes may be complicated by reproductive malignancies including ovarian cancer in CNC, breast and endometrial cancer in CD, breast malignancies in NF1, and malignant sex-cord stromal tumors in PJS.
Genomic Medicine Institute, Taussig Cancer Institute, Stanley Shalom Zielony Nursing Institute, Division of Medical Oncology, Divisions of Human Genetics, Endocrinology and Metabolism, Comprehensive Cancer Center, Departments of Genetics and Genome Sciences, Epidemiology and Biostatistics, CASE Comprehensive Cancer Center, Lerner Research Institute
Genomic Medicine Institute, Taussig Cancer Institute, Stanley Shalom Zielony Nursing Institute, Division of Medical Oncology, Divisions of Human Genetics, Endocrinology and Metabolism, Comprehensive Cancer Center, Departments of Genetics and Genome Sciences, Epidemiology and Biostatistics, CASE Comprehensive Cancer Center, Lerner Research Institute
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Genomic Medicine Institute, Taussig Cancer Institute, Stanley Shalom Zielony Nursing Institute, Division of Medical Oncology, Divisions of Human Genetics, Endocrinology and Metabolism, Comprehensive Cancer Center, Departments of Genetics and Genome Sciences, Epidemiology and Biostatistics, CASE Comprehensive Cancer Center, Lerner Research Institute
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Genomic Medicine Institute, Taussig Cancer Institute, Stanley Shalom Zielony Nursing Institute, Division of Medical Oncology, Divisions of Human Genetics, Endocrinology and Metabolism, Comprehensive Cancer Center, Departments of Genetics and Genome Sciences, Epidemiology and Biostatistics, CASE Comprehensive Cancer Center, Lerner Research Institute
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Genomic Medicine Institute, Taussig Cancer Institute, Stanley Shalom Zielony Nursing Institute, Division of Medical Oncology, Divisions of Human Genetics, Endocrinology and Metabolism, Comprehensive Cancer Center, Departments of Genetics and Genome Sciences, Epidemiology and Biostatistics, CASE Comprehensive Cancer Center, Lerner Research Institute
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Genomic Medicine Institute, Taussig Cancer Institute, Stanley Shalom Zielony Nursing Institute, Division of Medical Oncology, Divisions of Human Genetics, Endocrinology and Metabolism, Comprehensive Cancer Center, Departments of Genetics and Genome Sciences, Epidemiology and Biostatistics, CASE Comprehensive Cancer Center, Lerner Research Institute
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Genomic Medicine Institute, Taussig Cancer Institute, Stanley Shalom Zielony Nursing Institute, Division of Medical Oncology, Divisions of Human Genetics, Endocrinology and Metabolism, Comprehensive Cancer Center, Departments of Genetics and Genome Sciences, Epidemiology and Biostatistics, CASE Comprehensive Cancer Center, Lerner Research Institute
Genomic Medicine Institute, Taussig Cancer Institute, Stanley Shalom Zielony Nursing Institute, Division of Medical Oncology, Divisions of Human Genetics, Endocrinology and Metabolism, Comprehensive Cancer Center, Departments of Genetics and Genome Sciences, Epidemiology and Biostatistics, CASE Comprehensive Cancer Center, Lerner Research Institute
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Genomic Medicine Institute, Taussig Cancer Institute, Stanley Shalom Zielony Nursing Institute, Division of Medical Oncology, Divisions of Human Genetics, Endocrinology and Metabolism, Comprehensive Cancer Center, Departments of Genetics and Genome Sciences, Epidemiology and Biostatistics, CASE Comprehensive Cancer Center, Lerner Research Institute
Genomic Medicine Institute, Taussig Cancer Institute, Stanley Shalom Zielony Nursing Institute, Division of Medical Oncology, Divisions of Human Genetics, Endocrinology and Metabolism, Comprehensive Cancer Center, Departments of Genetics and Genome Sciences, Epidemiology and Biostatistics, CASE Comprehensive Cancer Center, Lerner Research Institute
Genomic Medicine Institute, Taussig Cancer Institute, Stanley Shalom Zielony Nursing Institute, Division of Medical Oncology, Divisions of Human Genetics, Endocrinology and Metabolism, Comprehensive Cancer Center, Departments of Genetics and Genome Sciences, Epidemiology and Biostatistics, CASE Comprehensive Cancer Center, Lerner Research Institute
Genomic Medicine Institute, Taussig Cancer Institute, Stanley Shalom Zielony Nursing Institute, Division of Medical Oncology, Divisions of Human Genetics, Endocrinology and Metabolism, Comprehensive Cancer Center, Departments of Genetics and Genome Sciences, Epidemiology and Biostatistics, CASE Comprehensive Cancer Center, Lerner Research Institute
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Along with breast and endometrial cancers, thyroid cancer is a major component cancer in Cowden syndrome (CS). Germline variants in SDHB/C/D (SDHx) genes account for subsets of CS/CS-like cases, conferring a higher risk of breast and thyroid cancers over those with only germline PTEN mutations. To investigate whether SDHx alterations at both germline and somatic levels occur in apparently sporadic breast cancer and differentiated thyroid cancer (DTC), we analyzed SDHx genes in the following four groups: i) 48 individuals with sporadic invasive breast adenocarcinoma for germline mutation; ii) 48 (expanded to 241) DTC for germline mutation; iii) 37 pairs DTC tumor-normal tissues for germline and somatic mutation and mRNA expression levels; and iv) data from 476 patients in the Cancer Genome Atlas thyroid carcinoma dataset for validation. No germline SDHx variant was found in a pilot series of 48 breast cancer cases. As germline SDHx variants were found in our pilot of 48 thyroid cancer cases, we expanded to three series of DTC comprising a total 754 cases, and found 48 (6%) with germline SDHx variants (P<0.001 compared with 0/350 controls). In 513 tumors, we found 27 (5%) with large somatic duplications within chromosome 1 encompassing SDHC. Both papillary and follicular thyroid tumors showed consistent loss of SDHC/D gene expression (P<0.001), which is associated with earlier disease onset and higher pathological-TNM stage. Therefore, we conclude that both germline and somatic SDHx mutations/variants occur in sporadic DTC but are very rare in sporadic breast cancer, and overall loss of SDHx gene expression is a signature of DTC.
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Ovarian cancer accounts for 5% of all cancer deaths in Western countries and is the most frequent cause of gynaecologic cancer mortality. The incidence varies with age between 1% and 14% with a peak rate in the eighth decade, and in the majority of cases, the disease has already spread beyond the pelvic cavity at time of diagnosis. Although in the last decades the introduction of cisplatin-based chemotherapy resulted in an improvement of patient survival, the percentage of recurrent disease is high even in those patients who achieve a complete response to chemotherapy, so that more than 80% of patients with advanced stage of disease die within 5 years (Copeland & Gershenson 1986). At present the prognostic characterisation of ovarian cancer patients, based on clinico-pathological parameters, such as stage, histology, grade and residual tumour after surgery, seems to be inadequate, since patients with similar clinico- pathological characteristics often experienced different clinical outcome. Therefore, the identification of biological factors related to tumour aggressiveness could be relevant in order to identify patients with different prognosis and chance to respond to chemotherapy, thus allowing the selection, at time of initial diagnosis, of high risk patients needing more aggressive therapy or alternative treatment, and a closer follow-up. Among the biological parameters proposed as possible prognostic factors in ovarian cancer much attention has been focused on endocrine factors and especially on steroid hormones and their receptors. Although several epidemiological and in vitro evidences have demonstrated that, similarly to breast and endometrial cancer, ovarian cancer cell biology could be influenced by the biochemical pathways promoted by the interaction of estrogens and progesterone with their specific receptors (ER, PR) conflicting data have been reported about the possible clinical role of ER and PR in this neoplasm. This review is aimed: a) to summarise the informations about the influence of steroid hormones and their receptors in the biology of ovarian cancer in in vitro models as well as in primary tumours;b) to investigate the association of steroid hormone receptor expression with the clinico-pathological parameters and the clinical outcome in ovarian cancer patients.c) to report the data of the literature about the rationale and the results of endocrine therapy in ovarian cancer.
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Cancer Society, cancer of the reproductive tract will account for 12% of all female cancers (79 480 of 662 870 estimated cases) and ~15% of female cancer-related mortalities (28 910 of 275 000 estimated cases). Endometrial cancer is the most common
Department of Medical and Clinical Genetics, Department of Cell and Molecular Biology, Department of Mathematical Statistics, Institute of Biomedicine, University of Gothenburg, Sahlgrenska Academy, SE 40530 Gothenburg, Sweden
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Department of Medical and Clinical Genetics, Department of Cell and Molecular Biology, Department of Mathematical Statistics, Institute of Biomedicine, University of Gothenburg, Sahlgrenska Academy, SE 40530 Gothenburg, Sweden
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Introduction Endometrial cancer is the most frequently diagnosed gynecological malignancy in the western world with an estimated incidence of 15–20 cases per 100 000 women per year ( Esteller et al . 1999 , Ryan et al . 2005 ). Endometrial
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sarcoma ( ACOG 2006 ). Recent data from Iqbal et al . (2012) showed that the risk ratio (RR) for endometrial cancer is low (RR: 1.19) in women receiving TAM therapy who are <50 years old but is significantly increased in those older than 50 years old
