darpp-32 and its truncated variant t-darpp have antagonistic effects on breast cancer cell growth and herceptin resistancedarpp-32及其截断变体t-darpp对抗对乳腺癌细胞生长和赫赛汀阻力的影响.pdfVIP

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2017-09-01 发布于上海
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darpp-32 and its truncated variant t-darpp have antagonistic effects on breast cancer cell growth and herceptin resistancedarpp-32及其截断变体t-darpp对抗对乳腺癌细胞生长和赫赛汀阻力的影响.pdf

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darpp-32 and its truncated variant t-darpp have antagonistic effects on breast cancer cell growth and herceptin resistancedarpp-32及其截断变体t-darpp对抗对乳腺癌细胞生长和赫赛汀阻力的影响

Darpp-32 and Its Truncated Variant t-Darpp Have Antagonistic Effects on Breast Cancer Cell Growth and Herceptin Resistance Long Gu, Sarah Waliany, Susan E. Kane* Division of Tumor Cell Biology, Beckman Research Institute of City of Hope, Duarte, California, United States of America Abstract Background: Herceptin (trastuzumab) is a humanized monoclonal antibody that is approved for the treatment of metastatic breast cancer patients whose tumors overexpress Her2 (erbB2/neu). Up to 70% of Her2-positive breast cancers demonstrate a response to Herceptin-based therapies, but resistance almost inevitably arises within a year of the initial response. To help understand the mechanism of Herceptin resistance, we isolated clonal variants of Her2-positive BT474 human breast cancer cells (BT/HerR) that are highly resistant to Herceptin. These cell lines exhibit sustained PI3K/Akt signaling as an essential component of Herceptin-resistant proliferation. Several genes in the protein kinase A (PKA) signaling network have altered expression in BT/HerR cells, including PPP1R1B, which encodes a 32 kDa protein known as Darpp-32 and its amino-terminal truncated variant, t-Darpp. The purpose of the current work was to determine the role of Darpp-32 and t-Darpp in Herceptin resistance. Methodology and Results: We determined expression of Darpp-32 and t-Darpp in BT/HerR cells selected for resistance to Herceptin. Subsequently, cDNAs encoding the two isoforms of Darpp-32 were transfected, separately and together, into Her2-positive SK-Br-3 breast cancer cells. Transfected cells were tested for resistance to Herceptin and Herceptin-mediated dephosphorylation of Akt. DNA binding activity by the cAMP response element binding protein (CREB) was also measured. We found that BT/HerR cells overexpressed t-Darpp but not Darpp-32. Moreover, t-Darpp overexpression in SK-Br-3 cells was sufficient