Genetically engineered mouse models of PI3K signaling in breast cancer

Klarenbeek, Sjoerd; Miltenburg, Martine H. van; Jonkers, Jos

doi:10.1016/j.molonc.2013.02.003

Cited by 33 publications

(29 citation statements)

References 147 publications

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“…Studies using mouse models have confirmed the importance of PI3K signaling in breast cancer (16). Transgenic mice that overexpress mutant PIK3CA in conjunction with HER2/neu recapitulate resistance to anti-HER2/neu therapies (17), and conditionally overexpressed mutant PIK3CA in the mammary gland gives rise to tumors at long latency that regress upon oncogene withdrawal (18).…”

mentioning

confidence: 95%

Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

Ebbesen

Scaltriti

Bialucha

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Loss of the tumor suppressor gene PTEN is implicated in breast cancer progression and resistance to targeted therapies, and is thought to promote tumorigenesis by activating PI3K signaling. In a transgenic model of breast cancer, Pten suppression using a tetracyclineregulatable short hairpin (sh)RNA cooperates with human epidermal growth factor receptor 2 (HER2/neu), leading to aggressive and metastatic disease with elevated signaling through PI3K and, surprisingly, the mitogen-activated protein kinase (MAPK) pathway. Restoring Pten function is sufficient to down-regulate both PI3K and MAPK signaling and triggers dramatic tumor regression. Pharmacologic inhibition of MAPK signaling produces similar effects to Pten restoration, suggesting that the MAPK pathway contributes to the maintenance of advanced breast cancers harboring Pten loss.

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mentioning

confidence: 95%

Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

Ebbesen

Scaltriti

Bialucha

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Numerous studies have demonstrated that well over half of breast cancers have genetic changes in components of the phosphatidylinositol-3-kinase (PI3K) signaling cascade, predicted to result in pathway activation [1–5]. These genomic changes include amplification, mutation or activation of receptor tyrosine kinases (HER2, EGFR), mutation or amplification of the catalytic subunit ( PIK3CA ), mutation of amplification of AKT1 , or loss of inhibition, impacting the PIK3R1 regulatory subunit, or phosphatase and tensin homolog ( PTEN ) function [2–5]. Considerable efforts have been directed to pharmacologic targeting of aberrant PI3K pathway activity [2–4, 6].…”

Section: Introductionmentioning

confidence: 99%

“…Activating ‘hotspot’ point mutations in PIK3CA are present in about 25% of invasive breast cancers, and are even further enriched in luminal-A cancers including invasive lobular carcinoma [1–5]. Accumulating data from a number of different studies shows that concurrent invasive and in-situ breast carcinoma (ductal carcinoma in-situ, DCIS) in the same patient frequently harbor identical PIK3CA mutations [7–11].…”

Section: Introductionmentioning

confidence: 99%

Multiplexed imaging reveals heterogeneity of PI3K/MAPK network signaling in breast lesions of known PIK3CA genotype

Jacob

Gray

Troxell

et al. 2016

Breast Cancer Res Treat

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Purpose Activating genetic changes in the phosphatidylinositol-3-kinase (PI3K) signaling pathway are found in over half of invasive breast cancers (IBC). Previously, we discovered numerous hotspot PIK3CA mutations in proliferative breast lesions. Here, we investigate the spatial nature of PI3K pathway signaling and its relationship with PI3K genotype in breast lesions. Methods We identified PI3K phosphosignaling network signatures in columnar cell change (CCL), usual ductal hyperplasia (UDH), ductal carcinoma in situ (DCIS) and IBC in 29 lesions of known PIK3CA genotype from 10 human breast specimens using a hyperspectral-based multiplexed tissue imaging platform (MTIP) to simultaneously quantitate PI3K/MAPK pathway targets (pAKT473, pAKT308, pPRAS40, pS6, and pERK) in FFPE tissue, with single cell resolution. Results We found that breast lesional epithelia contained spatially heterogeneous patterns of PI3K pathway phosphoprotein signatures, even within microscopic areas of CCL, UDH, DCIS and IBC. Most lesions contained 3–12 unique phosphoprotein signatures within the same microscopic field. The dominant phosphoprotein signature for each lesion was not well-correlated with lesion genotype or lesion histology, yet samples from the same patient tended to group together. Further, 5 UDH/CCL lesions across different patients had a common phosphosignature at the epithelial-stromal interface (possible myoepithelial cells) that was distinct from both the adjacent lesional epithelium, and distinct from adjacent stroma. Conclusion We present the first spatial mapping of PI3K phosphoprotein networks in proliferative breast lesions, and demonstrate complex PI3K signaling heterogeneity that defies simple correlation between PIK3CA genotype and phosphosignal pattern.

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“…AKT1 lies downstream of Phosphoinositide-3-Kinase (PI3K) signaling. This pathway can play numerous roles in carcinogenesis (Klarenbeek, et al 2013). To explore the role of AKT1 activation in breast cancer, a genetically engineered mouse model with expression of an artificially constitutively activated form of AKT1 targeted to mammary epithelium using the MMTV promoter was generated ( MMTV-myrAkt1 mice) (Blanco-Aparicio, et al 2007) (Table 1D).…”

Section: Carcinogen Exposure Can Promote Development Of Erα+ Mammary mentioning

confidence: 99%

Genetically engineered ERα-positive breast cancer mouse models

Dabydeen¹,

Furth²

2014

Endocrine-Related Cancer

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The majority of human breast cancers are ER+ but this has proven challenging to model in genetically engineered mice. This review summarizes information on twenty-one mouse models that develop ER+ mammary cancer. Where available, information on cancer pathology and gene expression profiles is referenced to assist in understanding which histological subtype of ER+ human cancer each model might represent. Esr1, Ccdn1, prolactin, TGFα, AIB1, Espl1, and Wnt1 over-expression, Pik3ca gain of function, as well as loss of p53 or loss of Stat1 are associated with ER+ mammary cancer. Treatment with the PPARγ agonist efatutazone in a mouse with Brca1 and p53 deficiency and DMBA exposure in combination with an activated myristoylated form of AKT1 also induce ER+ mammary cancer. A spontaneous mutant in nude mice that develops metastatic ER+ mammary cancer is included. Age of cancer development ranges from three to 26 months and the percentages of cancers that are ER+ vary from 21% to 100%. Not all models are characterized as to their estrogen dependency and/or response to anti-hormonal therapy. Strain backgrounds include C57Bl/6, FVB, BALB/c, 129S6/SvEv, CB6F1 and NIH nude. Most models have only been studied on one strain background. In summary while a range of models is available for studies of pathogenesis and therapy of ER+ breast cancers, many could benefit from further characterization and opportunity for development of new models remains.

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Genetically engineered mouse models of PI3K signaling in breast cancer

Cited by 33 publications

References 147 publications

Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

Multiplexed imaging reveals heterogeneity of PI3K/MAPK network signaling in breast lesions of known PIK3CA genotype

Genetically engineered ERα-positive breast cancer mouse models

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