Cryptococcal osteomyelitis of the skull in a liver transplant patient.

Cryptococcus neoformans is an opportunistic fungal pathogen and an important cause of morbidity and mortality in immunocompromised patients. We report a case of osteomyelitis caused by C. neoformans in a liver transplant recipient who presented with a headache and scalp lump after sustaining mild head trauma. There was no evidence of central nervous system involvement or dissemination. This is the first known case report of isolated cryptococcal osteomyelitis in a liver transplant recipient.

ERbeta in breast cancer--onlooker, passive player, or active protector?

The role of estrogen exposure in breast cancer risk is well-documented, and both estrogen synthesis and actions through the estrogen receptor (ER) have been targeted by therapies to control hormone-dependent breast cancer. The discovery of a second ER form and its therapeutic implications sparked great interest. Both the original ERalpha and the more recently identified ERbeta subtypes bind and respond similarly to many physiological and pharmacological ligands. However, differences in phytoestrogen binding have been noted, and subtype-specific ligands have been developed. Cell-based assays show that ERbeta and its variants are generally less active on gene transcription than ERalpha, and may influence ERalpha activity; however, both gene- and cell-specific responses occur, and nongenomic activities are less well explored. Specific ligands, and methods to disrupt or eliminate receptor subtype expression in animal and cell models, demonstrate that the ERs have both overlapping and distinct biological functions. Overall, in cell-based studies, ERalpha appears to play a predominant role in cell proliferation, and ERbeta is suggested to be antiproliferative. The potential for distinct populations of breast tumors to be identified based on ER subtype expression, and to exhibit distinct clinical behaviors, is of greatest interest. Several studies suggest that the majority of ER-positive tumors contain both subtypes, but that some tumors contain only ERbeta and may have distinct clinical behaviors and responses. Expression of ERbeta together with ERalpha favors positive responses to endocrine therapy in most studies, and additional studies to determine if the addition of ERbeta to ERalpha as a tumor marker is of clinical benefit are warranted. In contrast, the positive association between ERbeta and HER2 expression in high-grade ERalpha-negative breast cancer does not favor positive responses to endocrine therapy. Expression of ERbeta in specific clinical subpopulations, and the potential for therapies targeting ERbeta specifically, is discussed.

Physical and functional interactions between Cas and c-Src induce tamoxifen resistance of breast cancer cells through pathways involving epidermal growth factor receptor and signal transducer and activator of transcription 5b.

High expression of the adaptor molecule Cas has been linked to resistance to the antiestrogen tamoxifen, both in tissue culture and in human tumors. The aim of this study was to elucidate the mechanism(s) by which overexpression of Cas confers resistance to tamoxifen. Cas overexpression in MCF-7 breast cancer cells was shown to alleviate both tamoxifen-mediated growth inhibition and induction of apoptosis. This enhancement of cell proliferation/survival occurred in the absence of detectable effects on estrogen receptor (ER) transcriptional activity under conditions where tamoxifen was present, indicating that Cas-dependent tamoxifen resistance is not the result of a switch to an ER-negative phenotype or enhanced responses to the partial agonist activity of tamoxifen. Instead, we present evidence, suggesting that Cas promotes tamoxifen resistance by deregulation of alternative cell proliferation pathways, particularly those mediated through enhanced c-Src protein tyrosine kinase activity arising from Cas/c-Src interactions. Overexpression of Cas was found to drive endogenous c-Src into complex with Cas, a process that has been shown previously to cause up-regulation of c-Src tyrosine kinase activity. MCF-7 cells overexpressing Cas exhibited increased phosphorylation of two c-Src substrates, Tyr845 in the kinase domain of the epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription (STAT) 5b. Importantly, Cas-dependent protection from the antiproliferative effects of tamoxifen was reversed by the expression of dominant inhibitory variants of these substrates (Y845F EGFR and COOH-terminally truncated STAT5b). Based on these findings, we suggest that the Cas/c-Src/EGFR/STAT5 signaling axis is a major regulator of tamoxifen-resistant breast cancer cell growth and survival.