The Ras/Raf/MEK/ERK pathway conveys growth factor and mitogen signalling to control the phosphorylation of a plethora of substrates regulating proliferation, survival, and migration. The Ras signalling pathway is frequently associated with poor prognosis and drug resistance in various cancers including those of the blood, breast and prostate. Activation of the downstream effector ERK does not always occur via a linear cascade of events; complicating the targeting of this pathway therapeutically. This work describes a novel positive feedback loop where the cell cycle regulatory factor Spy1 (RINGO; gene SPDYA) activates ERK1/2 in a MEK-independent fashion. Spy1 was originally isolated for the ability to stimulate Xenopus oocyte maturation via a MAPK-signalling pathway and is known to override apoptosis triggered by the DNA damage response. We demonstrate that mammalian Spy1-mediated ERK activation increases ligand-independent phosphorylation and activation of estrogen receptor α, correlating with a decrease in tamoxifen sensitivity. This could define a novel druggable mechanism driving proliferation and resistance in select cancers.
BackgroundThrombin activatable fibrinolysis inhibitor (TAFI) is a plasma zymogen, which can be converted to activated TAFI (TAFIa) through proteolytic cleavage by thrombin, plasmin, and most effectively thrombin in complex with the endothelial cofactor thrombomodulin (TM). TAFIa is a carboxypeptidase that cleaves carboxyl terminal lysine and arginine residues from protein and peptide substrates, including plasminogen-binding sites on cell surface receptors. Carboxyl terminal lysine residues play a pivotal role in enhancing cell surface plasminogen activation to plasmin. Plasmin has many critical functions including cleaving components of the extracellular matrix (ECM), which enhances invasion and migration of cancer cells. We therefore hypothesized that TAFIa could act to attenuate metastasis.MethodsTo assess the role of TAFIa in breast cancer metastasis, in vitro migration and invasion assays, live cell proteolysis and cell proliferation using MDA-MB-231 and SUM149 cells were carried out in the presence of a TAFIa inhibitor, recombinant TAFI variants, or soluble TM.ResultsInhibition of TAFIa with potato tuber carboxypeptidase inhibitor increased cell invasion, migration and proteolysis of both cell lines, whereas addition of TM resulted in a decrease in all these parameters. A stable variant of TAFIa, TAFIa-CIIYQ, showed enhanced inhibitory effects on cell invasion, migration and proteolysis. Furthermore, pericellular plasminogen activation was significantly decreased on the surface of MDA-MB-231 and SUM149 cells following treatment with various concentrations of TAFIa.ConclusionsTaken together, these results indicate a vital role for TAFIa in regulating pericellular plasminogen activation and ultimately ECM proteolysis in the breast cancer microenvironment. Enhancement of TAFI activation in this microenvironment may be a therapeutic strategy to inhibit invasion and prevent metastasis of breast cancer cells.
Glucocorticoids, such as dexamethasone (Dex), are used to prevent common side effects induced by chemotherapy and are heavily prescribed for solid cancers such as breast cancer. There is substantial pre-clinical data to support that Dex activation of the glucocorticoid receptor overrides chemotherapy-induced apoptosis in breast cancer cell lines. These findings are compounded by a recent study demonstrating that increased glucocorticoid receptor activation by endogenous stress hormones increased breast cancer heterogeneity and metastasis. Our study is the first to use both in vitro and in vivo models to thoroughly compare the Dex response on the migration of multiple estrogen receptor negative (ER-) and ER+ cancer cell lines. ER+ and ER- breast cancer cell lines were studied to compare their endogenous glucocorticoid activity as well as their metastatic ability in response to Dex treatment. We show that in the ER- breast cancer lines, Dex increases cell numbers, invasiveness, and migration, while decreasing apoptotic ability. Furthermore, we show that following Dex treatment, ER- breast cancer lines migrate further in an in vivo zebrafish model in comparison to ER+ cell lines. The use of ROR1 antibody to block WNT signaling diminished the metastatic properties of ER- cells, however recombinant WNT5A alone was not sufficient to induce migration. Taken together, we demonstrate that Dex treatment exacerbates the metastatic potential of ER- but not ER+ cells. These findings add to the growing body of data stressing the potential adverse role of endogenous and synthetic glucocorticoids in breast cancer biology.
Barrier materials used in medical gloves and condoms to prevent the penetration of infectious agents are of utmost importance for the preservation of public health. Surrogate viruses have proven effective as conservative measures of infectious potential. Previous work has tested the integrity of barrier materials exposed to a host of pressures and stresses, however none have tested the effects of pH exposure mimicking that prevailing through coitus. We optimized the use of bacteriophage ФX174 and PCR detection to conduct a pilot study on the effects of pH on the viral penetration of latex condoms. Our results suggest that exposure of condoms to acidic pH ranges of physiological significance increases the frequency of condom failure rate. This proof of principal work supports the need for a larger study to investigate the significance of these effects over a wide range of condom brands.
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