NOTCH1 PEST domain variants are responsive to standard of care treatments despite distinct transformative properties in a breast cancer model
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Karen Cravero1,*, Morgan V. Pantone2,*, Dong Ho Shin2,*, Riley Bergman2, Rory Cochran1, David Chu1, Daniel J. Zabransky1, Swathi Karthikeyan1, Ian G. Waters1, Natasha Hunter1, D. Marc Rosen1, Kelly Kyker-Snowman1, W. Brian Dalton1, Berry Button1, Dan Shinn1, Hong Yuen Wong2, Joshua Donaldson2, Paula J. Hurley2, Sarah Croessmann2 and Ben Ho Park2
1 The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
2 Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
* These authors contributed equally to this work
|Ben Ho Park,||email:||firstname.lastname@example.org|
Keywords: NOTCH1; TNBC; breast cancer; PEST
Received: December 15, 2021 Accepted: February 07, 2022 Published: February 16, 2022
Activating variants in the PEST region of NOTCH1 have been associated with aggressive phenotypes in human cancers, including triple-negative breast cancer (TNBC). Previous studies suggested that PEST domain variants in TNBC patients resulted in increased cell proliferation, invasiveness, and decreased overall survival. In this study, we assess the phenotypic transformation of activating NOTCH1 variants and their response to standard of care therapies. AAV-mediated gene targeting was used to isogenically incorporate 3 NOTCH1 variants, including a novel TNBC frameshift variant, in two non-tumorigenic breast epithelial cell lines, MCF10A and hTERT-IMEC. Two different variants at the NOTCH1 A2241 site (A2441fs and A2441T) both demonstrated increased transformative properties when compared to a non-transformative PEST domain variant (S2523L). These phenotypic changes include proliferation, migration, anchorage-independent growth, and MAPK pathway activation. In contrast to previous studies, activating NOTCH1 variants did not display sensitivity to a gamma secretase inhibitor (GSI) or resistance to chemotherapies. This study demonstrates distinct transformative phenotypes are specific to a given variant within NOTCH1 and these phenotypes do not correlate with sensitivities or resistance to chemotherapies or GSIs. Although previous studies have suggested NOTCH1 variants may be prognostic for TNBC, our study does not demonstrate prognostic ability of these variants and suggests further characterization would be required for clinical applications.
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