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Studies utilizing different model systems have been conducted to systematically determine the molecular pathways affected by tamoxifen and estradiol in vitro and in vivo.

These studies have indicated that, although there is an overlap between the tamoxifen- and estradiol-induced gene expression profiles, tamoxifen also regulates its own specific set of genes in endometrial medical library. In a study by Tamm-Rosenstein et al (55), the endometrial Ishikawa cancer cell line was treated with tamoxifen or estradiol for 12 h, followed by RNA-sequencing.

Tamoxifen exposure altered the expression of 1013 medical library. Notably, while tamoxifen is often considered an agonist to estrogen in endometrial cells, the transcriptome results indicate that tamoxifen is both antagonistic and agonistic in the Ishikawa cell line. Similarly, a study utilizing primary cultures of human endometrial epithelial cultures showed that the majority of genes altered by tamoxifen treatment for 24 hrs were estrogen-independent (56).

Fong et medical library (13) injected a single dose of tamoxifen or ethinylestradiol to immature ovariectomized mice, and observed a significant increase in uterine wet weight after 24 h. Microarray analysis revealed that medical library and ethinylestradiol target genes overlapped but tamoxifen also medical library regulated genes associated medical library cell growth and proliferation, cytoskeletal organization, extracellular matrix modification, nucleotide synthesis, DNA replication, protein synthesis and turnover, lipid metabolism, glycolysis and immunological responses (13).

Notably, these investigators found that tamoxifen uses the same set of cell cycle genes as estradiol to promote cell proliferation in endometrial tissue, however, it does so to a lesser extent (57). Medical library results obtained through these methods aid in the identification of immediate targets of tamoxifen on endometrial cells. However, the association of endometrial cancer incidence rate with duration of tamoxifen exposure indicates that medical library exposure of tamoxifen has additional promoting effects on endometrial carcinogenesis.

As endometrial carcinogenesis is a progressive and not a sudden event, short-term exposure of endometrial cells to tamoxifen is not likely to reveal all of the signaling medical library that are critical for tamoxifen-promoted endometrial cancer. To understand the effects of long-term tamoxifen exposure on endometrial tissue, analyses of gene expression profile from large scale clinical data and experiments with long-term treatment of tamoxifen are required.

To date, only small scale studies comparing the gene expression profiles of tamoxifen-associated and sporadic endometrial cancers from patient samples have been undertaken.

However, another study with stage-matched patient tissue microarray revealed that gene expression profiles in endometrial tumors are different увидеть больше tamoxifen users compared with non-users (59).

Unsupervised clustering of all genes in all samples revealed that tumors from patients who had used tamoxifen clustered together, and were separate from samples of those who had never used tamoxifen. This study identified 256 differently expressed genes, the majority of which were tamoxifen-specific. Furthermore, these genes have also been shown to be upregulated and modulate tamoxifen-resistant breast cancer cells, indicating that long-term treatment with tamoxifen may stimulate similar gene networks to promote cancer progression in endometrial cells and overcome sensitivity in breast cancer cells.

The medical library of medical library resistance in breast cancer has demonstrated that the UPR signaling pathway is often activated by endocrine therapeutic interventions (60). The UPR components such as XBP1 and GRP78 are highly expressed medical library endocrine-resistant breast cancer cells that have undergone long-term exposure to tamoxifen or faslodex (61,62).

Faslodex is a pure ER antagonist that activates the degradation of the receptor protein. The activated UPR is essential in regulating cell fate via modulation of apoptosis and autophagy in breast cancer cells (61). As the effects of long-term tamoxifen exposure on the induction of the UPR signaling pathway medical library breast cancer cells are often ER-independent, it is reasonable to predict that long-term tamoxifen exposure may induce UPR signaling in endometrial cells in a similar manner.

The activated UPR signaling may promote cell survival and evasion of apoptosis, which are essential for cancer progression in endometrial tissue. In breast cancer cells, GRP78 has been shown to modulate mTOR activity medical library promote autophagy (61).

A number of studies have suggested that the mTOR signaling pathway is important in tamoxifen-associated endometrial cancer. The mean expression of mTOR in tamoxifen-associated endometrial cancer medical library was significantly higher compared with the non-tamoxifen group (63). Addition of the mTOR inhibitor RAD001 (Everolimus) can prevent tamoxifen-associated endometrial hyperplasia in mice, and significantly decreases proliferating cell nuclear antigen staining promoted by tamoxifen in the epithelial and glandular cells (64).

In addition, RAD001 decreases endometrial stromal ссылка на подробности proliferation in the tamoxifen-treated mice, which is known to send paracrine signals to promote the proliferation of endometrial medical library cells (64). Further investigation to determine the role of EnR stress-UPR-mTOR-autophagy signaling pathway in tamoxifen-associated endometrial cancer, particularly following long-term exposure, is urgently required to provide amlodipinum for the development of cancer prevention strategies for patients taking tamoxifen.

The blockage of pathways that are essential for endocrine resistance in breast and tamoxifen-associated endometrial carcinogenesis is of tremendous value in clinical cancer prevention. As tamoxifen is a proven effective therapeutic and preventive drug for breast cancer, targeting the two medical library hurdles that limit its clinical usage is of significant benefit to breast cancer patients. The EnR stress-UPR signaling pathway may be an ideal target if proven to be critical for tamoxifen-associated endometrial cancer.

In addition, accumulating medical library indicates that the physiology and homeostasis of the EnR and UPR signaling pathway are associated with obesity.

Obesity is an established risk factor for both breast cancer and endometrial cancer. Therefore, in medical library to the direct effects on endocrine resistance in breast cancer and tamoxifen-induced endometrial cancer, blocking the UPR pathway has the potential to benefit tamoxifen users indirectly through inhibition адрес obesity.

Tamoxifen is the most widely used breast cancer therapy and preventative drug worldwide. Understanding the molecular mechanisms of tamoxifen-promoted endometrial cancer is essential to identify strategies to lower the risk of developing endometrial cancer for breast cancer patients being treated with tamoxifen.

The modulation of estrogenic pathways is important in mediating the medical library proliferation promoting effects of tamoxifen in endometrial medical library. In addition, tamoxifen is known to regulate gene targets that are independent of estrogen.

However, the tamoxifen-specific medical library targets or networks that are essential for long-term tamoxifen exposure-induced endometrial medical library remain to be determined.

Recent studies and our own data indicate that UPR and mTOR signaling may be significant in long-term tamoxifen exposure-induced endometrial cancer. As these two pathways are also major contributors to the mediation of endocrine resistance in breast cancer cells, targeting them may benefit tamoxifen-treated breast cancer patients by reducing endocrine resistance, as well as endometrial cancers following long-term usage.

Larger scale clinical gene profile data and long-term tamoxifen experiments with in vitro and in vivo animal studies are needed to further clarify the involvement of these two pathways and molecular mechanisms that are essential for tamoxifen-associated endometrial cancer. Longer Medical library Shorter (ATLAS) Collaborative Group: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial.

View Article : Google Scholar :2 Jordan VC: Tamoxifen: the herald of a new era of preventive therapeutics. J Natl Cancer Inst. Tamoxifen treatment for medical library cancer and risk of endometrial cancer: a case-control study. View Article : Google Scholar10 Garuti Medical library, Cellani F, Centinaio G, Sita G, Nalli G and Luerti M: Histopathologic behavior of endometrial hyperplasia during tamoxifen therapy medical library breast cancer.

View Article : Google Scholar11 Bland AE, Calingaert B, Secord AA, et medical library Relationship between tamoxifen use and high risk endometrial cancer histologic types. View Article : Google Scholar12 Shang Y and Brown M: Molecular determinants for the tissue specificity of SERMs.

View Article : Google Scholar20 Taylor AH, Kalathy V and Habiba Перейти на страницу Estradiol and tamoxifen enhance invasion of endometrial stromal cells in a three-dimensional coculture model of adenomyosis. View Article : Google Scholar21 Cooke PS, Buchanan DL, Young P, et al: Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium.

View Article : Google Scholar33 Fles R, Hoogendoorn WE, Platteel I, et al: Genomic profile of endometrial tumors depends on morphological subtype, not on tamoxifen exposure.

View Article : Google Scholar35 Lagarda H, Catasus L, Arguelles R, Matias-Guiu X and Prat J: K-ras mutations in endometrial carcinomas with microsatellite instability. View Article : Google Scholar38 Turbiner J, Moreno-Bueno G, Dahiya S, et al: Clinicopathological and molecular medical library of endometrial carcinoma associated with tamoxifen.

View Article : Medical library Scholar42 Hachisuga T, Miyakawa T, Tsujioka H, Horiuchi S, Emoto M and Kawarabayashi T: K-ras mutation in tamoxifen-related endometrial polyps.

Int J Gynecol Cancer.



05.08.2020 in 16:39 Даниил:
Хорошо сказано.

12.08.2020 in 12:48 neyvecastu:
Я думаю, что Вы допускаете ошибку. Давайте обсудим это. Пишите мне в PM, пообщаемся.