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

Ebbesen, Saya H.; Scaltriti, Maurizio; Bialucha, Carl U.; Morse, Natasha; Kastenhuber, Edward R.; Wen, Hannah Y.; Dow, Lukas E.; Baselga, José; Lowe, Scott W.

doi:10.1073/pnas.1523693113

Cited by 59 publications

(52 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Intrinsic or de novo acquired resistance to HER2‐therapies has been described (Rexer and Arteaga, 2012) and no screening test to predict resistance to these therapies is currently available. In previous experimental studies, as well as in breast cancer patients, the contribution of an inactivation of the PTEN gene to the development of resistance against HER2‐targeting therapies in patients with HER2‐positive tumors has been reported (Burnett et al., 2015; Ebbesen et al., 2016). Moreover, it has been suggested that mutations in the PIK3CA gene play an important role in mechanisms leading to this resistance (Ahmad et al., 2014).…”

Section: Discussionmentioning

confidence: 99%

Frequent detection of PIK3CA mutations in single circulating tumor cells of patients suffering from HER2‐negative metastatic breast cancer

et al. 2016

View full text Add to dashboard Cite

Modern technologies enable detection and characterization of circulating tumor cells (CTC) in peripheral blood samples. Thus, CTC have attracted interest as markers for therapeutic response in breast cancer. First studies have incorporated CTC analyses to guide therapeutic interventions and stratification of breast cancer patients. Aim of this study was to analyze characteristic features of CTC as biomarker for predicting resistance to HER2-targeted therapies. Therefore, CTC from metastatic breast cancer patients with HER2-negative primary tumors screened for the prospective randomized phase III trial DETECT III were explored for their HER2 status and the presence of PIK3CA mutations. Detection and characterization of HER2 expression of CTC were conducted with the CellSearch(®) system. Fifteen of 179 CTC-positive patients (8.4%) contained ≥1 CTC with strong HER2 expression. Genomic DNA from individual CTC isolated by micromanipulation was propagated by whole genome amplification and analyzed for PIK3CA mutations in exons 9 and 20 by Sanger sequencing. One or more CTC/7.5 mL were detected in 179/290 patients (61.7%). In 109 patients (34.8%), ≥5 CTC/7.5 mL were found. We detected at least one CTC with the mutation p.E542K, p.E545K, p.H1047R, p.H1047L or p.M1043V in 12/33 patients (36.4%). Thirty six of 114 CTC (31.6%) harbored one of these mutations. CTC in individual patients exhibited heterogeneity concerning PIK3CA mutations and HER2 expression. In conclusion, clinically relevant genomic aberrations such as mutations in the hotspot regions of exon 9 and 20 of the PIK3CA gene can be detected in single CTC and might provide insights into mechanisms of resistance to HER2-targeted therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

Frequent detection of PIK3CA mutations in single circulating tumor cells of patients suffering from HER2‐negative metastatic breast cancer

et al. 2016

View full text Add to dashboard Cite

show abstract

“…S3B; Muller et al 1988). Female MMTV-Neu mice develop multifocal palpable mammary tumors efficiently after pregnancy (Ebbesen et al 2016). We generated FVB-Tg(MMTV-ErbB2) NK1Mul/J/miR-424(322)/503 −/− animals (MMTV-NeumiR_KO) and compared the expression of IGF1R, BCL-2, and CDC25A in size-matched tumors (0.5-0.8 cc) with MMTV-Neu animals.…”

Section: Cdc25a Bcl-2 and Igf1r Oncogenes Are Up-regulated In Mir-4mentioning

confidence: 99%

miR-424(322)/503 is a breast cancer tumor suppressor whose loss promotes resistance to chemotherapy

et al. 2017

View full text Add to dashboard Cite

The female mammary gland is a very dynamic organ that undergoes continuous tissue remodeling during adulthood. Although it is well established that the number of menstrual cycles and pregnancy (in this case transiently) increase the risk of breast cancer, the reasons are unclear. Growing clinical and experimental evidence indicates that improper involution plays a role in the development of this malignancy. Recently, we described the miR-424(322)/503 cluster as an important regulator of mammary epithelial involution after pregnancy. Here, through the analysis of ∼3000 primary tumors, we show that miR-424(322)/503 is commonly lost in a subset of aggressive breast cancers and describe the genetic aberrations that inactivate its expression. Furthermore, through the use of a knockout mouse model, we demonstrate for the first time that loss of miR-424(322)/503 promotes breast tumorigenesis in vivo. Remarkably, we found that loss of miR-424(322)/503 promotes chemoresistance due to the up-regulation of two of its targets: BCL-2 and insulin-like growth factor-1 receptor (IGF1R). Importantly, targeted therapies blocking the aberrant activity of these targets restore sensitivity to chemotherapy. Overall, our studies reveal miR-424(322)/ 503 as a tumor suppressor in breast cancer and provide a link between mammary epithelial involution, tumorigenesis, and the phenomenon of chemoresistance.

show abstract

“…Oncogenic MAPK signaling results in the production of immunosuppressive factors (e.g., VEGF, IL-6 and IL-10), which inhibit the proliferation and activation status of tumor-specific T cells and DCs [91]. In line with this, loss of the tumor suppressor gene PTEN has been shown to correlate with resistance against cancer immunotherapies, through the enhanced signaling of both the MAPK and PI3K signaling cascades [92,93]. Activation of the PI3K-AKT-mTOR pathway can contribute to therapy resistance by directly promoting tumor cell proliferation and survival, as well as the upregulation of PD-L1 cell surface expression, thereby inhibiting the function of local effector T cells [94].…”

Section: Tumor Cell Intrinsic Primary Resistance Mechanismsmentioning

confidence: 93%

Future Challenges in Cancer Resistance to Immunotherapy

Elsas

Hall

Burg

2020

Cancers

View full text Add to dashboard Cite

Cancer immunotherapies, including checkpoint inhibitors, adoptive T cell transfer and therapeutic cancer vaccines, have shown promising response rates in clinical trials. Unfortunately, there is an increasing number of patients in which initially regressing tumors start to regrow due to an immunotherapy-driven acquired resistance. Studies on the underlying mechanisms reveal that these can be similar to well-known tumor intrinsic and extrinsic primary resistance factors that precluded the majority of patients from responding to immunotherapy in the first place. Here, we discuss primary and secondary immune resistance and point at strategies to identify potential new mechanisms of immune evasion. Ultimately, this may lead to improved immunotherapy strategies with improved clinical outcomes.

show abstract

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

Cited by 59 publications

References 44 publications

Frequent detection of PIK3CA mutations in single circulating tumor cells of patients suffering from HER2‐negative metastatic breast cancer

Frequent detection of PIK3CA mutations in single circulating tumor cells of patients suffering from HER2‐negative metastatic breast cancer

miR-424(322)/503 is a breast cancer tumor suppressor whose loss promotes resistance to chemotherapy

Future Challenges in Cancer Resistance to Immunotherapy

Contact Info

Product

Resources

About