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The HIV protease inhibitor Nelfinavir (NFV) inhibits PI3K/AKT and MAPK/ERK signaling pathways, emerging targets in thyroid cancers. We examined the effects of NFV on cancer cells that derived from follicular (FTC), papillary (PTC) and anaplastic (ATC) thyroid cancers. NFV (1–20 µM) was tested in FTC133, BCPAP and SW1736 cell lines. The effects of NFV on cell proliferation were determined in vitro using real-time microscopy and by flow cytometry. DNA damage, apoptotic cell death and expression of molecular markers of epithelial–mesenchymal transition (EMT) were determined by Western blot and real-time PCR. Real-time imaging demonstrated that NFV (10 µM) increased the time required for the cell passage through the phases of cell cycle and induced DNA fragmentation. Growth inhibitory effects of NFV were associated with the accumulation of cells in G0/G1 phase, downregulation of cyclin D1 and cyclin-dependent kinase 4 (CDK4). NFV also induced the expression of γH2AX and p53BP1 indicating DNA damage. Treatment with NFV (20 µM) resulted in caspase-3 cleavage in all examined cells. NFV (20 µM) decreased the levels of total and p-AKT in PTEN-deficient FTC133 cells. NFV had no significant effects on total ERK and p-ERK in BRAF-positive BCPAP and SW1736 cells. NFV had no effects on the expression of EMT markers (Twist, Vimentin, E- and N-Cadherin), but inhibited the migration and decreased the abilities of thyroid cancer cells to survive in non-adherent conditions. We conclude that NFV inhibits proliferation and induces DNA damage in thyroid cancer cell lines. Our in vitro data suggest that NFV has a potential to become a new thyroid cancer therapeutic agent.
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Estrogen receptor (ER)-positive breast cancers generally have a better prognosis and are often responsive to anti-estrogen therapy, which is the first example of a successful therapy targeted on a specific protein, the ER. Unfortunately ER-negative breast cancers are more aggressive and unresponsive to anti-estrogens. Other targeted therapies are thus urgently needed, based on breast cancer oncogene inhibition or suppressor gene activation as far as molecular studies have demonstrated the alteration of expression, or structure of these genes in human breast cancer. Using the MDA-MB.231 human breast cancer cell line as a model of ER-negative breast cancers, we are investigating two of these approaches in our laboratory. Our first approach was to transfect the ER or various ER-deleted variants into an ER-negative cell line in an attempt to recover anti-estrogen responsiveness. The unliganded receptor, and surprisingly estradiol, were both found to inhibit tumor growth and invasiveness in vitro and in vivo. The mechanisms of these inhibitions in ER-negative cancer cells are being studied, in an attempt to target the ER sequence responsible for such inhibition in these cancer cells. Another strategy is trying to inhibit the activity or expression of an oncogene specifically overexpressed in most breast cancers. This approach was recently shown by others to be efficient in breast cancer therapy with HER2-Neu oncogene amplification using Herceptin. Without excluding other molecular putative targets, we have focused our research on cathepsin D as a potential target, since it is often overexpressed in aggressive human breast cancers, including ER-negative tumors, and rarely associated with HER2-Neu amplification. Our first results obtained in vitro on cell lines and in vivo in tumor xenografts in nude mice, illustrate that the mode of action of cathepsin D in breast cancer is useful to guide the development of these therapies. In the past 20 years we have learned that the action of cathepsin D is complex and involves both intracellular and extracellular activities due to its proteolytic activity and to interactions with membrane components without catalytic activity. Each of these mechanisms could be potentially inhibited in an attempt to prevent tumor growth. Breast cancer is a very heterogeneous and multigenic disease and different targeted therapies adapted to each category of breast cancer are therefore required. Validated assays in the primary tumor of molecular markers such as ER, HER2-Neu and cathepsin D should help to predict which targeted therapy should be applied to cure breast cancer patients.
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Introduction Several molecular marker tests are available to refine the diagnosis of thyroid nodules with indeterminate cytology. Initially, these tests were classified as either ‘rule-in’ or ‘rule-out’ tests, depending on their ability to
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signaling and were predicted to affect prognosis. Correlation between phosphorylation and expression levels of these molecular markers and their significance for survival were analyzed to identify patients who need additional therapy, such as signal
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the molecular approaches to thyroid tumor diagnosis. In addition, some of the molecular markers presented have been long studied, such as RAS, RET, PPARG/PAX8, PIK3CA, TP53, TSHR, PTEN, GNAS, CTNNB1, AKT1 , whereas others have recently emerged as
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investigated and some molecular markers have been identified and proven to be clinically useful ( Xing et al . 2013 a ). These include diagnostically the gene expression classifier ( Alexander et al . 2012 ), genetic marker panel ( Nikiforov et al . 2011
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each subgroup of samples were characterized by their median values and ranges, rather than their mean values and coefficients of variation, and (b) relationships between the molecular markers and clinical and biological parameters were tested using the
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visualize the capacity of a given molecular marker to discriminate between two populations, in the absence of an arbitrary cutoff value, we summarized the data in a ROC (receiver operating characteristics) curve ( Hanley & McNeil 1982 ). These curves plot
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metastases, and a heterogeneous mass with a high unenhanced attenuation value (>20HU) after exclusion of pheochromocytoma. Positive predictive value of histological and molecular markers ( Weiss 1984 , Cibas et al. 1990
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require assessment of many variables and as yet have not been applied prospectively for diagnostic or prognostic purposes. Hendrik Lehnert presented evidence that molecular markers, such as expression of human telomerase reverse transcriptase and
