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Proteomic and Transcriptomic Profiling Identifies Mediators of Anchorage-Independent Growth and Roles of Inhibitor of Differentiation Proteins in Invasive Lobular Breast Cancer

View ORCID ProfileNilgun Tasdemir, Kai Ding, Kevin M. Levine, Tian Du, Emily A. Bossart, View ORCID ProfileAdrian V. Lee, Nancy E. Davidson, View ORCID ProfileSteffi Oesterreich
doi: https://doi.org/10.1101/543132
Nilgun Tasdemir
1Womens Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, Pittsburgh, PA 15213, USA
2Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
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  • ORCID record for Nilgun Tasdemir
Kai Ding
1Womens Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, Pittsburgh, PA 15213, USA
3Integrative Systems Biology Program, University of Pittsburgh, Pittsburgh, PA, USA
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Kevin M. Levine
1Womens Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, Pittsburgh, PA 15213, USA
4Department of Pathology, University of Pittsburgh School of Medicine, PA 15261, USA
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Tian Du
1Womens Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, Pittsburgh, PA 15213, USA
5School of Medicine, Tsinghua University, Beijing 100084, China
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Emily A. Bossart
1Womens Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, Pittsburgh, PA 15213, USA
2Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
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Adrian V. Lee
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Nancy E. Davidson
6Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
7University of Washington, Seattle WA 98195, USA
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Steffi Oesterreich
1Womens Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, Pittsburgh, PA 15213, USA
2Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
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  • For correspondence: oesterreichs@upmc.edu
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Abstract

BACKGROUND Invasive lobular carcinoma (ILC) is a histological subtype of breast cancer with distinct molecular and clinical features from the more common subtype invasive lobular carcinoma (IDC). We have previously shown that human ILC cells lines have a remarkably unique ability to grow in ultra-low attachment (ULA) suspension cultures as compared to IDC cells, the mediators of which remain unknown.

METHODS Using flow cytometry and immunoblotting in human ILC and IDC cell lines, we measured levels of apoptosis and cell proliferation in attached (2D) and suspension (ULA) cultures. siRNA-mediated knockdown and pharmacological inhibitors were utilized to assess the effects of known regulators of anchorage-independence. Reverse Phase Protein Arrays and RNA-Sequencing were performed to identify novel proteomic and transcriptomic mediators of ULA growth in ILC cells.

RESULTS We show that human ILC cell lines exhibit enhanced anoikis resistance and cell proliferation in ULA cultures as compared to IDC cells. Transient restoration of E-cadherin did not impact the 2D or ULA growth of human ILC cell lines, while transient E-cadherin knockdown in IDC cells partially rescued their growth defect in ULA culture. Inhibition of the Rho/ROCK, p120-catenin or YAP/Hippo pathways previously implicated in anoikis resistance did not have a major effect on the ULA growth of ILC cells. Proteomic comparison of ILC and IDC cell lines identified unique induction of PI3K/Akt and p90-RSK pathways in ULA culture in ILC cells. Transcriptional profiling uncovered unique upregulation of the Inhibitors of Differentiation family transcription factors ID1 and ID3 in ILC ULA culture, the knockdown of which diminished anchorage-independent growth. We find that ID1 and ID3 expression is higher in human ILC tumors as compared to IDC and correlated with a worse disease-specific survival uniquely in the ILC cohort.

CONCLUSION Our comprehensive study of 2D and ULA growth in human ILC cell lines revealed anoikis resistance, cell proliferation and novel mediators of anchorage-independence and provides possible mechanistic insights and clinical implications for metastatic dissemination of ILC. High expression in human ILC tumors and association with clinical outcome implicate ID1 and ID3 as novel drivers and therapeutic targets for lobular breast cancer.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted February 07, 2019.
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Proteomic and Transcriptomic Profiling Identifies Mediators of Anchorage-Independent Growth and Roles of Inhibitor of Differentiation Proteins in Invasive Lobular Breast Cancer
Nilgun Tasdemir, Kai Ding, Kevin M. Levine, Tian Du, Emily A. Bossart, Adrian V. Lee, Nancy E. Davidson, Steffi Oesterreich
bioRxiv 543132; doi: https://doi.org/10.1101/543132
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Proteomic and Transcriptomic Profiling Identifies Mediators of Anchorage-Independent Growth and Roles of Inhibitor of Differentiation Proteins in Invasive Lobular Breast Cancer
Nilgun Tasdemir, Kai Ding, Kevin M. Levine, Tian Du, Emily A. Bossart, Adrian V. Lee, Nancy E. Davidson, Steffi Oesterreich
bioRxiv 543132; doi: https://doi.org/10.1101/543132

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