Dataset Information

Functional genomics identifies specific vulnerabilities in PTEN-deficient breast cancer.

ABSTRACT:

Background

Phosphatase and tensin homolog (PTEN) is one of the most frequently inactivated tumor suppressors in breast cancer. While PTEN itself is not considered a druggable target, PTEN synthetic-sick or synthetic-lethal (PTEN-SSL) genes are potential drug targets in PTEN-deficient breast cancers. Therefore, with the aim of identifying potential targets for precision breast cancer therapy, we sought to discover PTEN-SSL genes present in a broad spectrum of breast cancers.

Methods

To discover broad-spectrum PTEN-SSL genes in breast cancer, we used a multi-step approach that started with (1) a genome-wide short interfering RNA (siRNA) screen of ~ 21,000 genes in a pair of isogenic human mammary epithelial cell lines, followed by (2) a short hairpin RNA (shRNA) screen of ~ 1200 genes focused on hits from the first screen in a panel of 11 breast cancer cell lines; we then determined reproducibility of hits by (3) identification of overlaps between our results and reanalyzed data from 3 independent gene-essentiality screens, and finally, for selected candidate PTEN-SSL genes we (4) confirmed PTEN-SSL activity using either drug sensitivity experiments in a panel of 19 cell lines or mutual exclusivity analysis of publicly available pan-cancer somatic mutation data.

Results

The screens (steps 1 and 2) and the reproducibility analysis (step 3) identified six candidate broad-spectrum PTEN-SSL genes (PIK3CB, ADAMTS20, AP1M2, HMMR, STK11, and NUAK1). PIK3CB was previously identified as PTEN-SSL, while the other five genes represent novel PTEN-SSL candidates. Confirmation studies (step 4) provided additional evidence that NUAK1 and STK11 have PTEN-SSL patterns of activity. Consistent with PTEN-SSL status, inhibition of the NUAK1 protein kinase by the small molecule drug HTH-01-015 selectively impaired viability in multiple PTEN-deficient breast cancer cell lines, while mutations affecting STK11 and PTEN were largely mutually exclusive across large pan-cancer data sets.

Conclusions

Six genes showed PTEN-SSL patterns of activity in a large proportion of PTEN-deficient breast cancer cell lines and are potential specific vulnerabilities in PTEN-deficient breast cancer. Furthermore, the NUAK1 PTEN-SSL vulnerability identified by RNA interference techniques can be recapitulated and exploited using the small molecule kinase inhibitor HTH-01-015. Thus, NUAK1 inhibition may be an effective strategy for precision treatment of PTEN-deficient breast tumors.

SUBMITTER: Tang YC

PROVIDER: S-EPMC5863852 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Publications

Functional genomics identifies specific vulnerabilities in PTEN-deficient breast cancer.

Tang Yew Chung YC Ho Szu-Chi SC Tan Elisabeth E Ng Alvin Wei Tian AWT McPherson John R JR Goh Germaine Yen Lin GYL Teh Bin Tean BT Bard Frederic F Rozen Steven G SG

Breast cancer research : BCR 20180322 1

<h4>Background</h4>Phosphatase and tensin homolog (PTEN) is one of the most frequently inactivated tumor suppressors in breast cancer. While PTEN itself is not considered a druggable target, PTEN synthetic-sick or synthetic-lethal (PTEN-SSL) genes are potential drug targets in PTEN-deficient breast cancers. Therefore, with the aim of identifying potential targets for precision breast cancer therapy, we sought to discover PTEN-SSL genes present in a broad spectrum of breast cancers.<h4>Methods</h ...[more]

PMID: 29566768

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Project description:BackgroundThe discovery of breast cancer subtypes and subsequent development of treatments aimed at them has allowed for a great reduction in the mortality of breast cancer. But despite this progress, tumors with similar characteristics that belong to the same subtype continue to respond differently to the same treatment. Five subtypes of breast cancer, namely intrinsic subtypes, have been characterized to date based on their gene expression profiles. Among other characteristics, subtypes vary in their degree of intra-subtype heterogeneity. It is not clear, however, whether this heterogeneity is shared across all tumor traits. It is also unclear whether individual traits can be highly heterogeneous among a majority of homogeneous traits.ResultsWe employ network theory to uncover gene modules and accordingly consider them as tumor traits, which capture shared biological processes among the subtypes. We then use the β-diversity metric from ecology to quantify the heterogeneity in these gene modules. In doing so, we show that breast cancer heterogeneity is contained in gene modules and that this modular heterogeneity increases monotonically across the subtypes. We identify a core of two modules that are shared among all subtypes which contain nucleosome assembly and mammary morphogenesis genes, and a number of modules that are specific to subtypes. This modular heterogeneity, which increases with global heterogeneity, relates to tumor aggressiveness. Indeed, we observe that Luminal A, the most treatable of subtypes, has the lowest modular heterogeneity whereas the Basal-like subtype, which is among the hardest to treat, has the highest. Furthermore, our analysis shows that a higher degree of global heterogeneity does not imply higher heterogeneity for all modules, as Luminal B shows the highest heterogeneity for core modules.ConclusionsOverall, modular heterogeneity provides a framework with which to dissect cancer heterogeneity and better understand its underpinnings, thereby ultimately advancing our knowledge towards a more effective personalized cancer therapy.

Dataset Information

Functional genomics identifies specific vulnerabilities in PTEN-deficient breast cancer.

Background

Methods

Results

Conclusions

Publications

Functional genomics identifies specific vulnerabilities in PTEN-deficient breast cancer.

Similar Datasets

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