Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study

Simon, Dietmar; Körber, C.; Krausch, M.; Segering, J; Groth, Peter; Görges, R.; Grünwald, Frank; Hw, Müller-Gärtner; Schmutzler, Cornelia; Köhrle, Josef; Hd, Röher; Reiners, Christoph

doi:10.1007/s00259-001-0737-6

Cited by 167 publications

(105 citation statements)

References 37 publications

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“…In addition, the upregulatory effect of tRA on thyroid NIS expression was also previously established, and several clinical trials assessing RA redifferentiation therapy in dedifferentiated thyroid tumors and their metastasis were also previously started [33][34][35]. However, the potential of similar methods based on NIS activity in breast tumor cells still remains to be fully assessed.…”

Section: Identification Of a Novel Non-canonical Ere In Nis Promotermentioning

confidence: 99%

Unliganded estrogen receptor-α activates transcription of the mammary gland Na+/I− symporter gene

Alotaibi¹,

Yaman²,

Demirpençe³

et al. 2006

Biochemical and Biophysical Research Communications

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The function of sodium iodide symporter (Na + /I À symporter, or NIS) in mammary epithelial cells is essential for the accumulation of I À in milk; the newborn's first source of I À for thyroid hormone synthesis. Furthermore, increased mammary gland NIS expression has previously been shown in human breast cancer. Several hormones and factors including all-trans-retinoic acid (tRA) regulate the expression of NIS. In this study, using breast cancer cell lines, we established that tRA-responsive NIS expression is confined to estrogen receptor-a (ERa) positive cells and we investigated the role of ERa in the regulation of NIS expression. We showed that the suppression of endogenous ERa by RNA interference downregulates NIS expression in ERa positive mammary cells. Besides, in an ERa negative cell line, reintroduction of ERa resulted in the expression of NIS in a ligand-independent manner. We also identified a novel estrogen-responsive element in the promoter region of NIS that specifically binds ERa and mediates ERa-dependent activation of transcription. Our results indicate that unliganded ERa (apo-ERa) contributes to the regulation of NIS gene expression. In mammary gland lactocytes, sodium/iodide (Na + /I À ) symport via NIS is required to secrete I À in mother's milk [1]. I À in milk is used by the newborn in thyroid hormone biosynthesis, and thus it plays an essential role in post-natal development of skeletal muscles, nervous system, and lungs [2]. In vivo experiments in mice have previously demonstrated that in normal physiology, NIS expression is strictly linked to mammary development in gestation, and to lactation [1]. Non-lactating mammary gland tissue in female mice does not express NIS unless animals receive subcutaneous oxytocin treatments for three consecutive days. On the other hand, a similar treatment in ovariectomized mice is not sufficient for NIS upregulation. In these surgically treated animals, administration of 17-b-estradiol (E2) together with oxytocin is essential for functional expression of NIS. The fact that E2 treatment was only essential in ovariectomized animals, whereas lactogenic hormones were sufficient for functional NIS expression in surgically untreated mice, suggested that ovary functions and endogenous estrogens are essential in upregulating NIS expression [1]. Unlike in non-lactating mammary gland tissue, in transgenic mice bearing experimental breast cancers triggered by Erb-B2/neu and ras oncogenes, functional expression of NIS significantly increases [1]. In the same study, human breast cancer specimens were also analyzed, and an increased NIS expression was detected in human invasive breast cancer and ductal carcinoma in situ, as compared to no expression of NIS in healthy breast samples obtained from reductive mammoplasty operations [1].Recent studies with an ERa+ mammary cell line model, MCF-7, have led to the identification of additional hormones or ligands that control transcriptional regulation of NIS. In this cell line, the symporter gene was shown to be indu...

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Section: Identification Of a Novel Non-canonical Ere In Nis Promotermentioning

confidence: 99%

Unliganded estrogen receptor-α activates transcription of the mammary gland Na+/I− symporter gene

Alotaibi¹,

Yaman²,

Demirpençe³

et al. 2006

Biochemical and Biophysical Research Communications

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“…By reactivating tissue-specific genes, a differentiating therapy provides a target for tissue-specific therapy. There are hopes that retinoic acid and other agents may induce differentiation in thyroid cancer (Simon et al, 2002). Alternatively, recombinant TSH can induce the uptake of high-dose 131 iodine to ablate thyroid tissue (Berg et al, 2002).…”

Section: Tissue-selective Therapymentioning

confidence: 99%

Prospective strategies to enforce selectively cell death in cancer cells

Blagosklonny

2004

Oncogene

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Although induction of apoptosis (cell death mediated by caspases) determines response to cancer therapy, this approach is limited by lack of selectivity in available apoptosis-inducing agents. Furthermore, most cancers, almost by definition, are resistant to apoptosis, growth arrest and cell senescence. Then, how can anticancer agents kill cancer cell without unacceptable toxicity to a patient? The potential therapeutic approaches range from selective inhibition of antiapoptotic pathways, antiangiogenic therapy, tissue-selective therapy (including immunotherapy) to exploitation of, for example, drug resistance, oncoprotein addiction, unrestricted cell cycles, hypermitogenic and hypoxic features of cancer cells. These overlapping and complementary approaches rely on rational drug combinations (at mechanism-based doses and sequences) aimed at matching targets. To ensure killing of cancer cells selectively, we may combine apoptosis-and senescence-inducing agents with inhibitors of apoptosis (to protect normal cells), inhibitors of signal transduction with cell cycle-dependent chemotherapy, antiangiogenic agents with hypoxia-inducible factor-1 inhibitors, tissue-selective therapy with differentiating agents and activators of death receptors with chemotherapy. In theory, consecutive use of these drug combinations may control cancer.

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“…These patients are resistant to radioiodine therapy and have thus limited therapeutic alternatives. Treatment with 13-cis retinoic acid (RA) was shown to restore radioactive iodine uptake in thyroid cancer patients in two clinical trials (Grunwald et al, 1998;Simon et al, 2002). However, only one-third of the patients respond, prompting for a better understanding of thyroid oncogenesis and RA signalling pathways in thyroid cancer cells.…”

mentioning

confidence: 99%

Epigenetic patterns of the retinoic acid receptor β2 promoter in retinoic acid-resistant thyroid cancer cells

et al. 2007

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Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study

Cited by 167 publications

References 37 publications

Unliganded estrogen receptor-α activates transcription of the mammary gland Na+/I− symporter gene

Unliganded estrogen receptor-α activates transcription of the mammary gland Na+/I− symporter gene

Prospective strategies to enforce selectively cell death in cancer cells

Epigenetic patterns of the retinoic acid receptor β2 promoter in retinoic acid-resistant thyroid cancer cells

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