Fwd: Comparison of HER-2 and Hormone Receptor Expression in Primary Breast Cancers and Asynchronous Paired Metastases: Impact on Patient Management.

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From: HubMed - breast cancer <rssfwd@rssfwd.com>
Date: Fri, Jul 25, 2008 at 11:44 PM
Subject: Comparison of HER-2 and Hormone Receptor Expression in Primary Breast Cancers and Asynchronous Paired Metastases: Impact on Patient Management.
To: mesothelioma77@gmail.com


[1]Oncologist. 2008 Jul 23;
Guarneri V, Giovannelli S, Ficarra G, Bettelli S, Maiorana A, Piacentini F, Barbieri E, Dieci MV, D'Amico R, Jovic G, Conte P

Introduction. The assessment of hormone receptors (HRs) and human epidermal growth factor receptor (HER)-2 is necessary to select patients who are candidates for hormonal and anti-HER-2 therapy. The evaluation of these parameters is generally carried out in primary tumors and it is not clear if reassessment in metastatic lesions might have an impact on patient management. The primary aim of this analysis was to compare HER-2 and HR status in primary tumors versus metastatic sites in breast cancer patients. Patients and Methods. Seventy-five patients with available samples from primary tumors and paired metastases were included. HER-2 status was evaluated by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH); HR status was assessed by IHC. Results. Nineteen percent of primary tumors were HER-2 positive; 77% were HR positive. Sites of biopsied or resected metastases were: locoregional soft tissues (n = 30), liver (n = 20), central nervous system (n = 5), bone (n = 5), pleura (n = 4), distant soft tissues (n = 3), abdomen (stomach, colon, peritoneum) (n = 3), bronchus (n = 3), and bone marrow (n = 2). For paired metastases, the HER-2 status was unchanged in 84% of cases; two patients changed from positive to negative, while 10 patients converted from negative to positive (agreement, 84%; kappa = 0.5681). A change in HR status was observed in 16 cases (21%): nine cases from positive to negative and seven cases from negative to positive (agreement, 78.7%; kappa = 0.4158). Conclusions. Further studies are necessary to better define the level of discordance in HER-2 or HR status between primary tumors and paired metastases. However, a biopsy of metastatic disease can be recommended, if feasible with minimal invasiveness, because treatment options might change for a significant proportion of patients.



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Source: http://www.hubmed.org/display.cgi?uids=18650259
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Fwd: Biochemical and structural characterization of the Pak1- LC8 interaction.

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From: HubMed - breast cancer <rssfwd@rssfwd.com>
Date: Fri, Jul 25, 2008 at 11:44 PM
Subject: Biochemical and structural characterization of the Pak1- LC8 interaction.
To: mesothelioma77@gmail.com


[1]J Biol Chem. 2008 Jul 23;
Lightcap CM, Sun S, Lear JD, Rodeck U, Polenova T, Williams JC

PP21-activated kinase-1 (Pak1) and the dynein light chain, LC8, are overexpressed in breast cancer, and their direct interaction has been proposed to regulate tumor cell survival. These effects have been attributed in part to Pak1-mediated phosphorylation of LC8 at serine 88 (S88). However, LC8 is homodimeric which renders S88 inaccessible. Moreover, Pak1 does not contain a canonical LC8 binding sequence compared to other characterized LC8 binding sequences. Together, these observations raise the question whether the Pak1/LC8 interaction is distinct, i.e. enabled by a unique interface independent of LC8 dimerization. Herein, we present results from biochemical, NMR and crystallographic studies that show Pak1 (residues 212 to 222) binds to LC8 along the same groove as canonical LC8 interaction partners (e.g., nNOS, BimL). Using LC8 point mutants K36P and T67A, we were able to differentiate Pak1 from canonical LC8 binding sequences and identify a key hydrogen bond network that compensates for the loss of the conserved glutamine in the consensus sequence. We also show that the target binding interface formed through LC8 dimerization is required to bind to Pak1 and precludes phosphorylation of LC8 at S88. Consistent with this observation, in vitro phosphorylation assays using activated Pak1 fail to phosphorylate LC8. While these results define structural details of the Pak1/LC8 interaction and suggest a hierarchy of target binding affinities, they do not support the current model whereby Pak1 binds to and subsequently phosphorylates LC8 to promote anchorage independent growth. Rather, they suggest that LC8 binding modulates Pak1 activity and/or nuclear localization.



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Source: http://www.hubmed.org/display.cgi?uids=18650427
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