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Start Over Author "Blawski R" Publisher american association for cancer research
2 results on '"Blawski R"'

1. A Unique FOXA1-Associated Chromatin State Dictates Therapeutic Resistance in Lobular Breast Cancer.

Author

Blawski R and Toska E

Subjects
Chromatin genetics, Drug Resistance, Neoplasm genetics, Female, Hepatocyte Nuclear Factor 3-alpha genetics, Humans, Receptors, Estrogen genetics, Receptors, Estrogen metabolism, Retrospective Studies, Tamoxifen pharmacology, Tamoxifen therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology, Carcinoma, Ductal, Breast pathology, Carcinoma, Lobular drug therapy, Carcinoma, Lobular genetics, Carcinoma, Lobular metabolism
Abstract

Invasive lobular carcinomas (ILC) are the second most common histologic subtype of breast cancer, accounting for up to 15% of cases. ILC is estrogen receptor (ER) positive, yet its biology is distinct from invasive ductal carcinomas (IDC), and retrospective analyses have indicated a poorer outcome with endocrine therapy. In this issue of Cancer Research, Nardone and colleagues investigated the mechanisms of this differential therapy response in ILC, which cannot be solely explained by the genetic profile of these tumors. The authors conducted a thorough examination of the epigenome of ILC compared with IDC in clinical and preclinical models and revealed an alternative chromatin accessibility state in ILC driven by the pioneer factor FOXA1. FOXA1 regulates its own expression in a feed-forward mechanism by binding to an ILC-unique FOXA1 enhancer site. This results in a FOXA1-ER axis that promotes the transcription of genes associated with tumor progression and tamoxifen resistance. Targeting the FOXA1 enhancer region blocks this transcriptional program and inhibits ILC proliferation. These results shed light on a new epigenetic mechanism driving ILC tumor progression and treatment resistance, which may have profound therapeutic implications. See related article by Nardone et al., p. 3673., (©2022 American Association for Cancer Research.)

Published
2022
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2. The Oncogenic PI3K-Induced Transcriptomic Landscape Reveals Key Functions in Splicing and Gene Expression Regulation.

Author

Ladewig E, Michelini F, Jhaveri K, Castel P, Carmona J, Fairchild L, Zuniga AG, Arruabarrena-Aristorena A, Cocco E, Blawski R, Kittane S, Zhang Y, Sallaku M, Baldino L, Hristidis V, Chandarlapaty S, Abdel-Wahab O, Leslie C, Scaltriti M, and Toska E

Subjects
Carcinogenesis genetics, Cell Line, Tumor, Class I Phosphatidylinositol 3-Kinases genetics, Female, Humans, Phosphatidylinositol 3-Kinase genetics, Phosphatidylinositol 3-Kinase metabolism, RNA Splicing genetics, Transcriptome, Breast Neoplasms pathology, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism
Abstract

The phosphoinositide 3-kinase (PI3K) pathway regulates proliferation, survival, and metabolism and is frequently activated across human cancers. A comprehensive elucidation of how this signaling pathway controls transcriptional and cotranscriptional processes could provide new insights into the key functions of PI3K signaling in cancer. Here, we undertook a transcriptomic approach to investigate genome-wide gene expression and transcription factor activity changes, as well as splicing and isoform usage dynamics, downstream of PI3K. These analyses uncovered widespread alternatively spliced isoforms linked to proliferation, metabolism, and splicing in PIK3CA-mutant cells, which were reversed by inhibition of PI3Kα. Analysis of paired tumor biopsies from patients with PIK3CA-mutated breast cancer undergoing treatment with PI3Kα inhibitors identified widespread splicing alterations that affect specific isoforms in common with the preclinical models, and these alterations, namely PTK2/FRNK and AFMID isoforms, were validated as functional drivers of cancer cell growth or migration. Mechanistically, isoform-specific splicing factors mediated PI3K-dependent RNA splicing. Treatment with splicing inhibitors rendered breast cancer cells more sensitive to the PI3Kα inhibitor alpelisib, resulting in greater growth inhibition than alpelisib alone. This study provides the first comprehensive analysis of widespread splicing alterations driven by oncogenic PI3K in breast cancer. The atlas of PI3K-mediated splicing programs establishes a key role for the PI3K pathway in regulating splicing, opening new avenues for exploiting PI3K signaling as a therapeutic vulnerability in breast cancer., Significance: Transcriptomic analysis reveals a key role for the PI3K pathway in regulating RNA splicing, uncovering new mechanisms by which PI3K regulates proliferation and metabolism in breast cancer. See related commentary by Claridge and Hopkins, p. 2216., (©2022 The Authors; Published by the American Association for Cancer Research.)

Published
2022
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