Cooperation between <i>Pik3ca</i> and p53 Mutations in Mouse Mammary Tumor Formation

Adams, Jessica R.; Xu, Keli; Liu, Jeff C.; Agamez, Natalia M. Ruiz; Loch, Amanda J.; Wong, Ruth G.; Wang, Wei; Wright, Katherine L.; Lane, Timothy F.; Zacksenhaus, Eldad; Egan, Sean E.

doi:10.1158/0008-5472.can-10-0738

Cited by 134 publications

(163 citation statements)

References 45 publications

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“…Both effects are linked to a slower rate of Stat3 C dephosphorylation in the nucleus, as well as to increased DNA binding affinity (32)(33)(34). The R26 Cre-conditional transgenic system has been used to express Pik3ca H1047R (13) were expressed together (H), mice developed mostly poorly differentiated adenocarcinomas, complex adenocarcinomas, scirrhous tubular carcinomas; a smaller number of acinar tumors, adenosquamous carcinomas, squamous cysts, keratoacanthomas, and adenomyoepitheliomas also formed. When K-Ras…”

Section: Resultsmentioning

confidence: 99%

“…Slides were rinsed in running tap water for 5 minutes and then mounted onto a Tecan FreedomEvo liquid-handling robot. Staining was performed according to standard procedures (13,27). Images were captured with an AxioCam HRm digital camera (Zeiss) and AxioVision (release 4.6.3) software.…”

Section: Histology and Immunostainingmentioning

confidence: 99%

“…Most mammary tumors that form in this model are metaplastic adenosquamous carcinomas or adenomyoepitheliomas. Pik3ca H1047R mice do not develop mammary tumors that mimic the much more common ERa þ luminal breast tumor types (13,14).…”

Section: Introductionmentioning

confidence: 98%

“…PIK3CA, which codes for the p110a catalytic subunit of Class I phosphoinositide 3-kinase (PI3K), is the most commonly mutated gene in ERa þ luminal tumors and in metaplastic breast cancer (8,12). We recently described the first mouse model for PIK3CA-mutant breast cancer (13). Most mammary tumors that form in this model are metaplastic adenosquamous carcinomas or adenomyoepitheliomas.…”

Section: Introductionmentioning

confidence: 99%

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Ras Signaling Is a Key Determinant for Metastatic Dissemination and Poor Survival of Luminal Breast Cancer Patients

et al. 2015

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Breast cancer is associated with alterations in a number of growth factor and hormone-regulated signaling pathways. Mouse models of metastatic breast cancer typically feature mutated oncoproteins that activate PI3K, Stat3, and Ras signaling, but the individual and combined roles of these pathways in breast cancer progression are poorly understood. In this study, we examined the relationship between oncogenic pathway activation and breast cancer subtype by analyzing mouse mammary tumor formation in which each pathway was activated singly or pairwise. All three oncogenes showed cooperation during primary tumor formation, but efficient dissemination was only dependent on Ras. In addition, transcriptional profiling demonstrated that Ras induced adenocarcinomas with molecular characteristics related to human basal-like and HER2 þ tumors. In contrast, Ras combined with PIK3CA H1047R

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Section: Resultsmentioning

confidence: 99%

Section: Histology and Immunostainingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Ras Signaling Is a Key Determinant for Metastatic Dissemination and Poor Survival of Luminal Breast Cancer Patients

et al. 2015

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“…In 2 mice, we observed microinvasion of the ovarian stroma, indicating that the epithelial proliferation was neoplastic despite the absence of definitive cytological evidence of malignancy. The inability of Pik3ca H1047R to induce ovarian tumorigenesis differs from transgenic mouse models of Pik3ca H1047R inducing lung and breast (20)(21)(22)(23) tumors, but these models are driven by overexpressed Pik3ca H1047R rather than mutation of the endogenous gene, as occurs in human tumors. Possibly, the ovary could be less susceptible to transformation via a single mutation compared with other tissue types.…”

Section: Resultsmentioning

confidence: 99%

An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice

et al. 2012

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Inhibitors of STAT3, β‐catenin, and IGF‐1R sensitize mouse PIK3CA‐mutant breast cancer to PI3K inhibitors

et al. 2017

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Although mutations in the phosphoinositide 3‐kinase catalytic subunit (PIK3CA) are common in breast cancer, PI3K inhibitors alone have shown modest efficacy. We sought to identify additional pathways altered in PIK3CA‐mutant tumors that might be targeted in combination with PI3K inhibitors. We generated two transgenic mouse models expressing the human PIK3CA‐H1047R‐ and the ‐E545K hotspot‐mutant genes in the mammary gland and evaluated their effects on development and tumor formation. Molecular analysis identified pathways altered in these mutant tumors, which were also targeted in multiple cell lines derived from the PIK3CA tumors. Finally, public databases were analyzed to determine whether novel pathways identified in the mouse tumors were altered in human tumors harboring mutant PIK3CA. Mutant mice showed increased branching and delayed involution of the mammary gland compared to parental FVB/N mice. Mammary tumors arose in 30% of the MMTV‐PIK3CA‐H1047R and in 13% of ‐E545K mice. Compared to MMTV‐Her‐2 transgenic mouse mammary tumors, H1047R tumors showed increased upregulation of Wnt/β‐catenin/Axin2, hepatocyte growth factor (Hgf)/Stat3, insulin‐like growth factor 2 (Igf‐2), and Igf‐1R pathways. Inhibitors of STAT3, β‐catenin, and IGF‐1R sensitized H1047R‐derived mouse tumor cells and PIK3CA‐H1047R overexpressing human HS578T breast cancer cells to the cytotoxic effects of PI3K inhibitors. Analysis of The Cancer Genome Atlas database showed that, unlike primary PIK3CA‐wild‐type and HER‐2+ breast carcinomas, PIK3CA‐mutant tumors display increased expression of AXIN2, HGF, STAT3, IGF‐1, and IGF‐2 mRNA and activation of AKT, IGF1‐MTOR, and WNT canonical signaling pathways. Drugs targeting additional pathways that are altered in PIK3CA‐mutant tumors may improve treatment regimens using PI3K inhibitors alone.

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Cooperation between Pik3ca and p53 Mutations in Mouse Mammary Tumor Formation

Cited by 134 publications

References 45 publications

Ras Signaling Is a Key Determinant for Metastatic Dissemination and Poor Survival of Luminal Breast Cancer Patients

Ras Signaling Is a Key Determinant for Metastatic Dissemination and Poor Survival of Luminal Breast Cancer Patients

An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice

Inhibitors of STAT3, β‐catenin, and IGF‐1R sensitize mouse PIK3CA‐mutant breast cancer to PI3K inhibitors

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