Deletion of PTEN promotes tumorigenic signaling, resistance to anoikis, and altered response to chemotherapeutic agents in human mammary epithelial cells.
Deletion of PTEN promotes tumorigenic signaling, resistance to anoikis, and altered response to chemotherapeutic agents in human mammary epithelial cells.
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DOI：
10.1158/0008-5472.can-09-1067
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发表时间：
2009-11-01
期刊：
影响因子：
11.2
通讯作者：
Bachman KE
中科院分区：
文献类型：
--
作者：
Vitolo MI;Weiss MB;Szmacinski M;Tahir K;Waldman T;Park BH;Martin SS;Weber DJ;Bachman KE
Many cancers, including breast cancer, harbor loss of function mutations in the catalytic domain of the PTEN phosphatase or have reduced PTEN expression through loss of heterozygosity (LOH) and/or epigenetic silencing mechanisms. However, specific phenotypic effects of PTEN inactivation in human cancer cells remain poorly defined without a direct causal connection between the loss of PTEN function and the development or progression of cancer. To evaluate the biological and clinical relevance of reduced or deleted PTEN expression, a novel in vitro model system was generated using human somatic cell knock-out technologies. Targeted homologous recombination allowed for a single and double allelic deletion which resulted in reduced and deleted PTEN expression, respectively. We determined that heterozygous loss of PTEN in the non-tumorigenic human mammary epithelial cell line, MCF-10A, was sufficient for activation of the PI3K/Akt and MAPK pathways, while the homozygous absence of PTEN expression led to a further increased activation of both pathways. The deletion of PTEN was able to confer growth factor-independent proliferation which was confirmed by the resistance of the PTEN−/− MCF-10A cells to small molecule inhibitors of the EGF receptor. However, neither heterozygous nor homozygous loss of PTEN expression was sufficient to promote anchorage-independent growth, but the loss of PTEN did confer apoptotic resistance to cell rounding and matrix detatchment. Finally, MCF-10A cells with the reduction or loss of PTEN showed increased susceptibility to the chemotherapeutic drug doxorubicin, but not paclitaxel.
