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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Breast cancer is now the most common malignancy diagnosed in women. Growth factor and estrogen receptors elicit tight regulation of breast tumor progression. Estrogen receptors occur in about two-thirds of breast tumors, and endocrine therapy targeted to these receptors is effective in a large proportion of tumors that express both estrogen and progesterone receptors. However, after an initial period of response to hormonal therapy, such as tamoxifen, most tumors develop resistance leading to disease relapse. Emerging data suggest that previously unsuspected interactions between growth factor and estrogen signaling pathways contribute to growth promotion in breast cancer. Targeting different components of this signaling axis may allow development of more effective and less toxic anti-hormone treatments for breast cancer. In recent clinical studies, anastrozole, letrozole and exemestane, inhibitors of the estrogen synthase, aromatase, have shown advantages over tamoxifen as treatment for advanced disease. Fulvestrant is a new type of estrogen receptor antagonist that down-regulates cellular levels of estrogen receptor and has no agonist activity. Due to its unique mode of action, fulvestrant may be an ideal candidate for combination treatment with inhibitors targeted to growth factor receptor signaling pathways. New understanding of estrogen receptor genes, gene transcripts and variants, post-translational modifications of receptor protein products and interactions with other signaling networks in tumor cells are leading us to unique targeted approaches in the hormonal therapy of breast cancer.
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PMID:New approaches to reverse resistance to hormonal therapy in human breast cancer. 1605 21

Prolonged exposure to 17beta-estradiol (E2) is a key etiological factor for human breast cancer. The biological effects and carcinogenic effects of E2 are mediated via estrogen receptors (ERs), ERalpha and ERbeta. Anti-estrogens, e.g. tamoxifen, and aromatase inhibitors have been used to treat ER-positive breast cancer. While anti-estrogen therapy is initially successful, a major problem is that most tumors develop resistance and the disease ultimately progresses, pointing to the need of developing alternative drugs targeting to other critical targets in breast cancer cells. We have identified that Na+, K+-ATPase, a plasma membrane ion pump, has unique/valuable properties that could be used as a potentially important target for breast cancer treatment: (a) it is a key player of cell adhesion and is involved in cancer progression; (b) it serves as a versatile signal transducer and is a target for a number of hormones including estrogens and (d) its aberrant expression and activity are implicated in the development and progression of breast cancer. There are several lines of evidence indicating that ouabain and related digitalis (the potent inhibitors of Na+, K+-ATPase) possess potent anti-breast cancer activity. While it is not clear how the suggested anti-cancer activity of these drugs work, several observations point to ouabain and digitalis as being potential ER antagonists. We critically reviewed many lines of evidence and postulated a novel concept that Na+, K+-ATPase in combination with ERs could be important targets of anti-breast cancer drugs. Modulators, e.g. ouabain and related digitalis could be useful to develop valuable anti-breast cancer drugs as both Na+, K+-ATPase inhibitors and ER antagonists.
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PMID:Sodium/potassium ATPase (Na+, K+-ATPase) and ouabain/related cardiac glycosides: A new paradigm for development of anti- breast cancer drugs? 1632 95

Large cell calcifying Sertoli cell tumors (LCCSCT) are associated with Carney complex and Peutz-Jeghers syndrome. The mechanisms linking these 2 genetic defects to the genesis of this tumor are obscure. Studies of CYP19 (aromatase) and transforming growth factor (TGF)-beta1 messenger RNA (mRNA) abundance, estrogen receptor (ER), TGFbeta1, and TGFbeta type II receptor (R) immunochemistry were carried out in the testis of a patient with this tumor to gain information on possible mechanisms of cell tumor development. Testicular tissue of a prepubertal patient, collected at gonadectomy, was separated into 2 macroscopically distinct fractions: tumoral nodules (Tu) and extratumoral, normal-looking testicular tissue (ExTu). The patient was a 9.5-year-old boy with a 5-year history of bilateral gynecomastia (Tanner stage 4), no pubic hair, incipient genital development, and bilateral testicular nodules. Multiple pigmented lesions of the skin were present. Bilateral mammectomy and gonadectomy was performed. RNA was extracted from Tu and ExTu for semiquantitative reverse transcriptase-polymerase chain reaction of CYP19 and TGFbeta1. Protein expression of ER, TGFbeta1, and TGFbeta type II R in Tu and ExTu was detected by immunohistochemistry. Cell proliferation was estimated by Ki-67 antigen immunochemistry and apoptosis using a modified TUNEL assay. Mean expression of aromatase and TGFbeta1 mRNAs in Tu was 6- and 2.3-fold higher than in ExTu, respectively (P<0.05). Tumoral cells exhibited ER staining with a predominant extranuclear localization. Positive staining of Sertoli cells in Tu was higher than in ExTu. TGFbeta1 immunostaining of the interstitial cells in Tu was higher than in ExTu. TGFbeta type II R immunostaining was detected in most Sertoli and interstitial cells, but intensity in ExTu was lower than in Tu. No significant difference was detected in the proliferation index, but in Tu, the percentage of Sertoli cells in apoptosis (1.4%) was significantly lower (P<0.01) than in ExTu (14.0%). The following hypothesis is proposed. The congenital gene defects of Carney complex or of Peutz-Jeghers syndrome might trigger a cascade of intracellular events that leads to overexpression of aromatase in Sertoli cells, favoring the development of a LCCSCT. At some point in the evolution of the disease, a mutational event might induce a higher expression of the ER. Also, TGFbeta1 protein expression is increased in neighboring cells. In this environment, TGFbeta1 might switch from tumor suppressor to oncogenic factor and, along with estrogen-ER complexes, might favor tumor progression by inhibiting apoptosis.
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PMID:High TGFbeta1, estrogen receptor, and aromatase gene expression in a large cell calcifying sertoli cell tumor (LCCSCT): implications for the mechanism of oncogenesis. 1694 77

Patients with advanced breast cancer frequently develop metastasis to bone. Bone metastasis results in intractable pain and a high risk of fractures due to tumor-driven bone loss (osteolysis), which is caused by increased osteoclast activity. Osteolysis releases bone-bound growth factors including transforming growth factor beta (TGF-beta). The widely accepted model of osteolytic bone metastasis in breast cancer is based on the hypothesis that the TGF-beta released during osteolytic lesion development stimulates tumor cell parathyroid hormone related protein (PTHrP), causing stromal cells to secrete receptor activator of NFkappaB ligand (RANKL), thus increasing osteoclast differentiation. Elevated osteoclast numbers results in increased bone resorption, leading to more TGF-beta being released from bone. This interaction between tumor cells and the bone microenvironment results in a vicious cycle of bone destruction and tumor growth. Bisphosphonates are commonly prescribed small molecule therapeutics that target tumor-driven osteoclastic activity in osteolytic breast cancers. In addition to bisphosphonate therapies, steroidal and non-steroidal antiestrogen and adjuvant therapies with aromatase inhibitors are additional small molecule therapies that may add to the arsenal for treatment of osteolytic breast cancer. This review focuses on a brief discussion of tumor-driven osteolysis and the effects of small molecule therapies in reducing osteolytic tumor progression.
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PMID:Breast cancer bone metastasis and current small therapeutics. 1716 Jul 9

Several studies suggested that aromatase could play an important role in tumor progression and prognosis in endometrial cancer because androstenedione is converted to estrogen by the enzyme. For better understanding of the aromatase expression in endometrial cancer and its relation to diverse clinicopathological parameters, we conducted this study. This study was carried out with 141 endometrial cancer patients, all of whom had undergone operations in our institution from 1993 to 2002. Paraffin-embedded tissue blocks were sectioned and immunostained with monoclonal antiaromatase antibody using human placental tissue as positive control. Clinicopathological variables of all patients were also reviewed. Despite quite a high aromatase expression in positive control, there was no endometrial cancer specimen showing the enzyme expression. Our result, although needs further investigation on the cause of the difference from other studies, suggested that aromatase might not have an important role in endometrial cancer.
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PMID:Aromatase expression was not detected by immunohistochemistry in endometrial cancer. 1740 19

Prostate cancer is the commonest non-skin cancer in men. Incidence and mortality rates of this tumor vary strikingly throughout the world. Although several factors have been implicated to explain this remarkable variation, lifestyle and dietary factors may play a dominant role, with sex hormones behaving as intermediaries between exogenous factors and molecular targets in development and progression of prostate cancer. Human prostate cancer is generally considered a paradigm of androgen-dependent tumor; however, estrogen role in both normal and malignant prostate appears to be equally important. The association between plasma androgens and prostate cancer remains contradictory and mostly not compatible with the androgen hypothesis. Similar evidence apply to estrogens, although the ratio of androgen to estrogen in plasma declines with age. Apart from methodological problems, a major issue is to what extent circulating hormones can be considered representative of their intraprostatic levels. Both nontumoral and malignant human prostate tissues and cells are endowed with key enzymes of steroid metabolism, including 17betahydroxysteroid dehydrogenase (17betaHSD), 5beta-reductase, 3alpha/3betaHSD, and aromatase. A divergent expression and/or activity of these enzymes may eventually lead to a differential prostate accumulation of steroid derivatives having distinct biological activities, as it occurs for hydroxylated estrogens in the human breast. Locally produced or metabolically transformed estrogens may differently affect proliferative activity of prostate cancer cells. Aberrant aromatase expression and activity has been reported in prostate tumor tissues and cells, implying that androgen aromatization to estrogens may play a role in prostate carcinogenesis or tumor progression. Interestingly, many genes encoding for steroid enzymes are polymorphic, although only a few studies have supported their relation with risk of prostate cancer. In animal model systems estrogens, combined with androgens, appear to be required for the malignant transformation of prostate epithelial cells. Although the mechanisms underlying the hormonal induction of prostate cancer in experimental animals remain uncertain, there is however evidence to support the assumption that long term administration of androgens and estrogens results in an estrogenic milieu in rat prostates and in the ensuing development of dysplasia and cancer. Both androgen and estrogen have been reported to stimulate proliferation of cultured prostate cancer cells, primarily through receptor-mediated effects. As for estrogens, the two major receptor types, ERalpha and ERbeta, are expressed in both normal and diseased human prostate, though with a different cellular localization. Since these two receptors are different in terms of ligand binding, heterodimerization, transactivation, and estrogen response element activity, it is likely that an imbalance of their expression may be critical to determine the ultimate estrogen effects on prostate cancer cells. In prostate cancer, ERbeta activation appears to limit cell proliferation directly or through ERalpha inhibition, and loss of ERbeta has been consistently associated with tumor progression. Several splicing variants of both ERalpha and ERbeta exist. Little is known about their expression and function in the human prostate, although reciprocal regulation and interaction with gene promoter both warrant further investigation. In summary, although multiple consistent evidence suggests that estrogens are critical players in human prostate cancer, their role has been only recently reconsidered, being eclipsed for years by an androgen-dominated interest.
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PMID:Estrogen and prostate cancer: an eclipsed truth in an androgen-dominated scenario. 1778 30

Epidemiological and experimental evidence implicates estrogens in the etiology and progression of breast cancer. The biosynthesis of estrogens from androgens is catalyzed by an enzymatic complex designated as aromatase (CYP19). Using quantitative real-time PCR and Western blot analysis, we demonstrated that trichostatin A (TSA) histone deacetylase inhibitor significantly reduced CYP19 transcript and protein contents in MCF-7 breast cancer cells. We also found that TSA lowered CYP19 transcript stability and significantly decreased the transcript's half-life from approximately 6h to 3.5h. Our results from experiments with a protein biosynthesis inhibitor suggest the involvement of an RNase and/or mRNA stabilization protein in CYP19 transcript stabilization. Since malignant tissue aromatase is a significant estrogen producer involved in breast tumor progression, our findings may have clinical implication.
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PMID:Trichostatin A down-regulates CYP19 transcript and protein levels in MCF-7 breast cancer cells. 1860 94

Adjuvant treatment with aromatase inhibitors (AIs) improves outcomes in postmenopausal women with hormone-sensitive early breast cancer compared with tamoxifen. However, AIs should not be used in premenopausal women because they can paradoxically increase estrogen secretion and may therefore stimulate tumor progression. In perimenopausal women undergoing treatment for breast cancer, it can be difficult to determine true menopausal status because adjuvant chemotherapy, tamoxifen, and gonadotropin-releasing hormone analogues can induce transient (or permanent) ovarian suppression. How can one determine whether these women are truly postmenopausal and therefore candidates for AI therapy? A panel of experts in the field of endocrine therapy in breast cancer met in Dubrovnik, Croatia, on October 23, 2006, to discuss this clinical dilemma. This report summarizes the conclusions and recommendations that arose from this discussion.
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PMID:Adjuvant endocrine therapy for perimenopausal women with early breast cancer. 1903 88

In order to evaluate the importance of estrogen production in tumor and surrounding tissues, we measured mRNA expression levels of 5 enzymes participating to estrogen synthesis in situ and 4 breast cancer-related proteins in 27 pairs of tumor and non-malignant tissues. Steroid sulfatase (STS) mRNA was more frequently detected in tumor tissues rather than in their non-malignant counterparts. Estrogen sulfotransferase (EST) was constantly expressed with high level not only in tumor tissues but also in their surrounding non-malignant counterparts. In contrast, mRNA expression levels of aromatase, and 17beta-hydroxysteroid dehydrogenase type I and II were relatively low and detected only in small proportion of the patients. We also measured the mRNA expression levels of the same nine genes in tumor tissues of 197 breast cancer patients, and analyzed relationship between the mRNA expression level and the clinicopathological parameters. The mRNA expression levels of STS, aromatase and erbB2 in tumor tissues increased as breast cancer progressed. The tumoral mRNA expression levels of STS, estrogen receptor beta, and erbB2 in patients with recurrence were higher than those in patients without recurrence. Upregulation of STS expression plays an important role in tumor progression of human breast cancer and is considered to be responsible for estrogen production in tumor and surrounding tissues.
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PMID:Expression level of enzymes related to in situ estrogen synthesis and clinicopathological parameters in breast cancer patients. 1915 87

Lung cancer has become increasingly common in women, and gender differences in the physiology and pathogenesis of the disease have suggested a role for estrogens. In the lung recent data have shown local production of estrogens from androgens via the action of aromatase enzyme and higher levels of estrogen in tumor tissue as compared with surrounding normal lung tissue. High levels of aromatase expression are also maintained in metastases as compared with primary tumors. Consistent with these findings, clinical studies suggest that aromatase expression may be a useful predictive biomarker for prognosis in the management of non-small cell lung cancer (NSCLC), the most common form of lung malignancy. Low levels of aromatase associate with a higher probability of long-term survival in older women with early stage NSCLC. Treatment of lung NSCLC xenografts in vivo with an aromatase inhibitor (exemestane) alone or combined with standard cisplatin chemotherapy elicits a significant reduction in tumor progression as compared to paired controls. Further, lung cancer progression is also governed by complex interactions between estrogen and growth factor signaling pathways to stimulate the growth of NSCLC as well as tumor-associated angiogenesis. We find that combination therapy with the multitargeted growth factor receptor inhibitor vandetanib and the estrogen receptor antagonist fulvestrant inhibit tumor growth more effectively than either treatment administered alone. Thus, incorporation of antiestrogen treatment strategies in standard antitumor therapies for NSCLC may contribute to improved patient outcome, an approach that deserves to be tested in clinical trials.
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PMID:Targeting aromatase and estrogen signaling in human non-small cell lung cancer. 1925 Feb 5


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