Project description:This study examined the effect of mutant PIK3CAH1047R expression in mammary subsets of preneoplastic mammary glands from K8-creERT2/PIK3CA H1047R mice Mammary cell subpopulations were isolated from K8-creERT2/PIK3CAH1047R and K8-creERT2 control animals 4 weeks after activation of PIK3CA H1047R transgene expression by Tamoxifen injection. Pooled mammary glands of 2-3 estrus-synchronized mice per genotype were sorted in 3 independent sortings and used for microarray analysis (20 samples in total).
Project description:This study examined the effect of mutant PIK3CAH1047R expression in mammary subsets of preneoplastic mammary glands from Lgr5-creERT2/PIK3CA H1047R mice Mammary cell subpopulations were isolated from Lgr5-creERT2/PIK3CA H1047R and Lgr5-creERT2 control animals 4 weeks after activation of PIK3CA H1047R transgene expression by Tamoxifen injection. Pooled mammary glands of 2-3 estrus-synchronized mice per genotype were sorted in 3 independent sortings and used for microarray analysis (24 samples in total).
Project description:This study examined the effect of mutant PIK3CAH1047R expression in mammary subsets of preneoplastic mammary glands from K8-creERT2/PIK3CA H1047R mice
Project description:This study examined the effect of mutant PIK3CAH1047R expression in mammary subsets of preneoplastic mammary glands from Lgr5-creERT2/PIK3CA H1047R mice
2015-08-12 | GSE59870 | GEO
Project description:PIK3CA(H1047R)-evoked breast tumorigenesis
Project description:Gain-of-function mutation of PIK3CA represents one of the most common oncogenic events in human malignancy, making PI3K an attractive target for cancer therapy. Despite the great promise of targeted therapy, drug resistance is likely to develop, causing treatment failure. To elucidate resistance mechanisms to PI3K-targeted therapy, we constructed a mouse model of breast cancer conditionally expressing PIK3CA-H1047R. Surprisingly, the majority of mammary tumors induced by PIK3CA-H1047R expression recurred following PIK3CA-H1047R inactivation. Genomic analyses of recurrent tumors revealed multiple lesions, including spontaneous focal amplification of c-Met or c-Myc. While amplification of c-Met allowed tumor survival dependent on activation of endogenous PI3K, tumors with amplification of c-Myc become independent of the PI3K pathway. Functional analyses further demonstrated that c-Myc contributed to tumors’ independence of oncogene and resistance to PI3K inhibition. Together, our data suggest that MYC elevation in tumors may be a potential mechanism conferring resistance to current PI3K-targeted therapies. Affymetrix SNP array analysis was performed with Mouse Diversity Genotyping Arrays (Affymetrix) on genomic DNA extracted from frozen biopsies of 6 recurrent mouse mammary tumor samples. Copy number analysis was performed for the mouse mammary tumors using genomic DNA from normal mammary tissue as the reference for copy number inference.
Project description:This study examined the gene expression profile of mammary tumors derived from Lgr5- and K8-positive cell-of-origins Mammary tumors and reference mammary glands from control mice were collected, cryo-homogenized, total RNA was isolated and analyzed by microarray (total 25 samples).
Project description:Gain-of-function mutation of PIK3CA represents one of the most common oncogenic events in human malignancy, making PI3K an attractive target for cancer therapy. Despite the great promise of targeted therapy, drug resistance is likely to develop, causing treatment failure. To elucidate resistance mechanisms to PI3K-targeted therapy, we constructed a mouse model of breast cancer conditionally expressing PIK3CA-H1047R. Surprisingly, the majority of mammary tumors induced by PIK3CA-H1047R expression recurred following PIK3CA-H1047R inactivation. Genomic analyses of recurrent tumors revealed multiple lesions, including spontaneous focal amplification of c-Met or c-Myc. While amplification of c-Met allowed tumor survival dependent on activation of endogenous PI3K, tumors with amplification of c-Myc become independent of the PI3K pathway. Functional analyses further demonstrated that c-Myc contributed to tumors’ independence of oncogene and resistance to PI3K inhibition. Together, our data suggest that MYC elevation in tumors may be a potential mechanism conferring resistance to current PI3K-targeted therapies.
