A 63-year-old Japanese woman was diagnosed with metastatic well-differentiated neuroendocrine carcinoma presenting as a perianal mass without an obvious primary site. Two years later, she presented with a breast mass determined on histologic examination to be the primary neuroendocrine carcinoma. The tumor was weakly positive for estrogen receptor and clearly originated in multifocal ductal carcinoma in situ. At the same time, she was found to have multiple metastases in bone and liver and, later, heart. Most studies report a relatively poor prognosis and limited treatment responsiveness for neuroendocrine breast carcinoma. Better understanding of the cellular origin and molecular pathogenesis of this relatively enigmatic rare disease is required.
[Show abstract][Hide abstract] ABSTRACT: Mammalian target of rapamycin (mTOR) signaling is a central regulator of protein translation, cell growth, and metabolism. Alterations of the mTOR signaling pathway are common in cancer, making mTOR a promising therapeutic target. In clinical trials, rapamycin analogs have shown modest response rates for most cancer types, including breast cancer. Therefore, there is an urgent need to better understand the mechanism of action of rapamycin to improve patient selection and to monitor pathway inhibition. To identify novel pharmacodynamic markers of rapamycin activity, we carried out transcriptional profiling of total and polysome-associated RNA in three breast cancer cell lines representing different subtypes. In all three cell lines, we found that rapamycin significantly decreased polysome-associated mRNA for stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzyme in monounsaturated fatty acid synthesis. Activators of mTOR increased SCD1 protein expression, whereas rapamycin, LY294002, and BEZ235 decreased SCD1 protein expression. Rapamycin decreased total SCD1 RNA expression without inducing a significant decline in its relative polysomal recruitment (polysome/total ratio). Rapamycin did not alter SCD1 mRNA stability. Instead, rapamycin inhibited SCD1 promoter activity and decreased expression of mature transcription factor sterol regulatory element binding protein 1 (SREBP1). Eukaryotic initiation factor 4E (eIF4E) small interfering RNA (siRNA) decreased both SCD1 and SREBP1 expression, suggesting that SCD1 may be regulated through the mTOR/eIF4E-binding protein 1 axis. Furthermore, SCD1 siRNA knockdown inhibited breast cancer cell growth, whereas overexpression increased growth. Taken together these findings show that rapamycin decreases SCD1 expression, establishing an important link between cell signaling and cancer cell fatty acid synthesis and growth.
Molecular Cancer Therapeutics 09/2010; 9(10):2770-84. DOI:10.1158/1535-7163.MCT-09-0980 · 5.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neuroendocrine tumours (NET) of the breast are rare. Diagnosis depends on close scrutiny of core- or excisional-biopsy specimens for characteristic growth patterns (papillary, nesting or mixed), which should trigger immunohistochemical staining for neuroendocrine markers (in particular chromogranin and synaptophysin). The diagnosis is confirmed if a) >50% of the tissue specimen demonstrate neuroendocrine markers and b) in-situ ductal carcinoma is identified and/or imaging modalities exclude extra-mammary sites. Our literature search including the non-English literature identified 66 articles with data on 123 cases, including our own. Oestrogen receptors are not diagnostic for NET's of the breast as they are found in tumours of non-mammary origin, too. Half of reported cases of neuroendocrine tumours have axillary lymph node involvement. Breast-conserving surgery (wide local excision ± axillary clearance) is commonly performed for suitable tumours. Chemotherapy regimens utilised are commonly either platinum- (as for small-cell cancers) or anthracycline-based (as for primary breast cancers). Best management remains unknown.
Breast (Edinburgh, Scotland) 12/2013; 23(2). DOI:10.1016/j.breast.2013.11.005 · 2.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Primary neuroendocrine breast carcinoma (NEBC) is a rare entity of breast cancer.
Presentation of case:
We herein report a case of right hepatectomy for a NEBC liver metastasis.
Little is known about its evolution, bilologic behavior and optimal treatment. Its malignant potential has been addressed in few reports, with cases of metachronous metastases in diverse sites, even years following treatment of the breast primarily.
Treating this kind of cancer implies both breast and hepatic surgery. Primary neuroendocrine breast carcinoma (NEBC) is a rare entity of breast cancer. Little is known about its evolution, biologic behavior and optimal treatment. Its malignant potential has been addressed in few reports, with cases of metachronous metastases in diverse sites, even years following treatment of the breast primarily. We herein report a case of right hepatectomy for a NEBC liver metastasis.
International Journal of Surgery Case Reports 06/2014; 5(8). DOI:10.1016/j.ijscr.2014.05.006
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