The EstroGene2.0 database for endocrine therapy response and resistance in breast cancer

Zheqi Li; Fangyuan Chen; Li Chen; Jiebin Liu; Danielle Tseng; Fazal Hadi; Soleilmane Omarjee; Kamal Kishore; Joshua Kent; Joanna Kirkpatrick; Clive D'Santos; Mandy Lawson; Jason Gertz; Matthew J Sikora; Donald P McDonnell; Jason S Carroll; Kornelia Polyak; Steffi Oesterreich; Adrian V Lee

doi:10.1038/s41523-024-00709-4

The EstroGene2.0 database for endocrine therapy response and resistance in breast cancer

NPJ Breast Cancer. 2024 Dec 19;10(1):106. doi: 10.1038/s41523-024-00709-4.

Authors

Zheqi Li^#^{1

2}, Fangyuan Chen^#^{3

4}, Li Chen^#⁵, Jiebin Liu^{4

6}, Danielle Tseng⁴, Fazal Hadi⁷, Soleilmane Omarjee⁸, Kamal Kishore⁸, Joshua Kent⁸, Joanna Kirkpatrick⁸, Clive D'Santos⁸, Mandy Lawson⁷, Jason Gertz⁹, Matthew J Sikora¹⁰, Donald P McDonnell¹¹, Jason S Carroll⁸, Kornelia Polyak^{1

2}, Steffi Oesterreich^{4

12}, Adrian V Lee^{13

14

15}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Department of Medicine, Harvard Medical School, Boston, MA, USA.
³ School of Medicine, Tsinghua University, Beijing, China.
⁴ Women's Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
⁵ Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA.
⁶ Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁷ AstraZeneca, The Discovery Centre, Biomedical Campus, Cambridge, UK.
⁸ Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK.
⁹ Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA.
¹⁰ Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹¹ Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
¹² Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
¹³ Women's Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. [email protected].
¹⁴ Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
¹⁵ Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].

^# Contributed equally.

Abstract

Endocrine therapies targeting the estrogen receptor (ER/ESR1) are the cornerstone to treat ER-positive breast cancers patients, but resistance often limits their effectiveness. Notable progress has been made although the fragmented way data is reported has reduced their potential impact. Here, we introduce EstroGene2.0, an expanded database of its precursor 1.0 version. EstroGene2.0 focusses on response and resistance to endocrine therapies in breast cancer models. Incorporating multi-omic profiling of 361 experiments from 212 studies across 28 cell lines, a user-friendly browser offers comprehensive data visualization and metadata mining capabilities ( https://estrogeneii.web.app/ ). Taking advantage of the harmonized data collection, our follow-up meta-analysis revealed transcriptomic landscape and substantial diversity in response to different classes of ER modulators. Endocrine-resistant models exhibit a spectrum of transcriptomic alterations including a contra-directional shift in ER and interferon signalings, which is recapitulated clinically. Dissecting multiple ESR1-mutant cell models revealed the different clinical relevance of cell model engineering and identified high-confidence mutant-ER targets, such as NPY1R. These examples demonstrate how EstroGene2.0 helps investigate breast cancer's response to endocrine therapies and explore resistance mechanisms.

Abstract

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