Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth.

We have previously demonstrated that oestrogen receptor alpha (ERalpha) modulates epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) signalling efficiency in a tamoxifen-resistant MCF-7 breast cancer cell line (Tam-R). In the present study we have investigated whether this cross-talk between EGFR/MAPK and ERalpha signalling pathways is bidirectional by examining the effects of EGFR/MAPK activity on ER functionality in the same cell line. Elevated expression levels of phosphorylated serine 118 (S118) ERalpha were observed in the Tam-R compared to the parental wild type MCF-7 cell line (WT-MCF-7) under basal growth conditions. Phosphorylation of ERalpha at S118 was regulated by the EGFR/MAPK pathway in Tam-R cells being increased in response to amphiregulin (AR) and inhibited by the selective EGFR tyrosine kinase inhibitor, gefitinib and the MEK1/2 inhibitor, PD184352. Recruitment of the co-activators p68 RNA helicase and SRC1 to ERalpha, oestrogen response element (ERE) activity and Tam-R cell growth were similarly EGFR/MAPK-regulated. Chromatin immunoprecipitation (ChIP) studies revealed that in Tam-R cells the ERalpha assembled on the AR gene promoter and this was associated with elevated basal expression of AR mRNA. Furthermore, AR mRNA expression was under the regulation of the EGFR/MAPK and ERalpha signalling pathways. Neutralising antibodies to AR inhibited EGFR/ERK1/2 activity, reduced S118 ERalpha phosphorylation and reduced AR mRNA expression in TAM-R cells. These findings suggest that ERalpha function in Tam-R cells is maintained as a consequence of EGFR/MAPK-mediated phosphorylation at serine residue 118 resulting in the generation of a self-propogating autocrine growth-regulatory loop through the ERalpha-mediated production of AR.

A comparison of zidovudine, didanosine, zalcitabine and no antiretroviral therapy in patients with advanced HIV disease.

Three nucleoside analogues, zidovudine (AZT), didanosine (ddI), and zalcitabine (ddC), are approved for use in the treatment of patients with HIV infection. This retrospective study compares the 3 drugs and examines the overall utility of antiretroviral therapy by way of comparisons to a no treatment (No Rx) group in patients with advanced HIV disease. Patients with advanced HIV disease were enrolled in didanosine (August 1989-December 1990) or zalcitabine (October 1990-February 1992) expanded access programmes; continued on zidovudine treatment despite fulfilling criteria for zidovudine failure or intolerance; or maintained on no antiretroviral treatment. Statistical analysis revealed that patients on nucleoside analogue therapy had fewer opportunistic infections (P = 0.001) than those who received no antiretroviral treatment. The Kaplan-Meier 12-month estimate of survival was significantly longer among patients who switched from zidovudine to zalcitabine but not among patients who switched to didanosine, when compared to the other 2 groups (P = 0.05).