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Exploratory investigation of PSCA-protein expression in primary breast cancer patients reveals a link to HER2/neu overexpression.

ABSTRACT: Prostate stem cell antigen (PSCA) has been suggested as biomarker and therapeutic target for prostate cancer. Recent advances showed that PSCA is up-regulated in other cancer entities, such as bladder or pancreatic cancer. However, the clinical relevance of PSCA-expression in breast cancer patients has not yet been established and is therefore addressed by the current study.PSCA-protein expression was assessed in 405 breast cancer patients, using immunohistochemistry (PSCA antibody MB1) and tissue microarrays.PSCA-expression was detected in 94/405 patients (23%) and correlated with unfavorable histopathological grade (p=0.011) and increased Ki67 proliferation index (p=0.006). We observed a strong positive correlation between PSCA-protein expression and HER2/neu receptor status (p<0.001). PSCA did not provide prognostic information in the analyzed cohort. Interestingly, the distribution of PSCA-expression among triple negative patients was comparable to the total population.We identified a subgroup of PSCA-positive breast cancer patients, which could be amenable for a PSCA-targeted therapy. Moreover, given that we found a strong positive correlation between PSCA- and HER/neu expression, targeting PSCA may provide an alternative therapeutic option in case of trastuzumab resistance.

SUBMITTER: Link T

PROVIDER: S-EPMC5589606 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Exploratory investigation of PSCA-protein expression in primary breast cancer patients reveals a link to HER2/neu overexpression.

Link Theresa T Kuithan Friederike F Ehninger Armin A Kuhlmann Jan Dominik JD Kramer Michael M Werner Andreas A Gatzweiler Axel A Richter Barbara B Ehninger Gerhard G Baretton Gustavo G Bachmann Michael M Wimberger Pauline P Friedrich Katrin K

Oncotarget 20170429 33

<h4>Background</h4>Prostate stem cell antigen (PSCA) has been suggested as biomarker and therapeutic target for prostate cancer. Recent advances showed that PSCA is up-regulated in other cancer entities, such as bladder or pancreatic cancer. However, the clinical relevance of PSCA-expression in breast cancer patients has not yet been established and is therefore addressed by the current study.<h4>Methods</h4>PSCA-protein expression was assessed in 405 breast cancer patients, using immunohistoche ...[more]

PMID: 28903367

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Project description:HER2/neu (HER2) and cyclin E are important prognostic indicators in breast cancer. As both are involved in cell cycle regulation we analyzed whether there was a direct interaction between the two. HER2 and cyclin E expression levels were determined in 395 breast cancer patients. Patients with HER2-overexpression and high levels of cyclin E had decreased 5-year disease-specific survival compared with low levels of cyclin E (14% versus 89%, P<0.0001). In vitro studies were performed in which HER2-mediated activity in HER2-overexpressing breast cancer cell lines was downregulated by transfection with HER2 small interfering RNA or treatment with trastuzumab. Cyclin E expression levels were determined by western blot analysis, and functional effects analyzed using kinase assays, MTT assays were used to assess cell viability as a marker of proliferation and fluorescence-activated cell sorting analysis was used to determine cell cycle profiles. Decreased HER2-mediated signaling resulted in decreased expression of cyclin E, particularly the low molecular weight (LMW) isoforms. Decreased HER2 and LMW cyclin E expression had functional consequences, including decreased cyclin E-associated kinase activity and decreased proliferation, because of increased apoptosis and an increased accumulation of cells in the G1 phase. In vivo studies performed in a HER2-overexpressing breast cancer xenograft model confirmed the effects of trastuzumab on cyclin E expression. Given the relationship between HER2 and cyclin E, in vitro clonogenic assays were performed to assess combination therapy targeting both proteins. Isobologram analysis showed a synergistic interaction between the two agents (trastuzumab targeting HER2 and roscovitine targeting cyclin E). Taken together, these studies show that HER2-mediated signaling effects LMW cyclin E expression, which in turn deregulates the cell cycle. LMW cyclin E has prognostic and predictive roles in HER2-overexpressing breast cancer, warranting further study of its potential as a therapeutic target.

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Exploratory investigation of PSCA-protein expression in primary breast cancer patients reveals a link to HER2/neu overexpression.

Publications

Exploratory investigation of PSCA-protein expression in primary breast cancer patients reveals a link to HER2/neu overexpression.

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