IGF1R constitutive activation expands luminal progenitors and influences lineage differentiation during breast tumorigenesis.

Authors

Susan M Farabaugh
Beate C Litzenburger
Ashuvinee Elangovan
Geoffrey Pecar
Lauren Walheim
Jennifer M Atkinson
Adrian V Lee

Publication/Presentation Date

7-1-2020

Abstract

Breast tumors display tremendous heterogeneity in part due to varying molecular alterations, divergent cells of origin, and differentiation. Understanding where and how this heterogeneity develops is likely important for effective breast cancer eradication. Insulin-like growth factor (IGF) signaling is critical for normal mammary gland development and function, and has an established role in tumor development and resistance to therapy. Here we demonstrate that constitutive activation of the IGF1 receptor (IGF1R) influences lineage differentiation during mammary tumorigenesis. Transgenic IGF1R constitutive activation promotes tumors with mixed histologies, multiple cell lineages and an expanded bi-progenitor population. In these tumors, IGF1R expands the luminal-progenitor population while influencing myoepithelial differentiation. Mammary gland transplantation with IGF1R-infected mammary epithelial cells (MECs) resulted in hyperplastic, highly differentiated outgrowths and attenuated reconstitution. Restricting IGF1R constitutive activation to luminal versus myoepithelial lineage-sorted MECs resulted in ductal reconstitutions co-expressing high IGF1R levels in the opposite lineage of origin. Using in vitro models, IGF1R constitutively activated MCF10A cells showed increased mammosphere formation and CD44+/CD24-population, which was dependent upon Snail and NFκB signaling. These results suggest that IGF1R expands luminal progenitor populations while also stimulating myoepithelial cell differentiation. This ability to influence lineage differentiation may promote heterogeneous mammary tumors, and have implications for clinical treatment.

Volume

463

Issue

1

First Page

77

Last Page

87

ISSN

1095-564X

Published In/Presented At

Farabaugh, S. M., Litzenburger, B. C., Elangovan, A., Pecar, G., Walheim, L., Atkinson, J. M., & Lee, A. V. (2020). IGF1R constitutive activation expands luminal progenitors and influences lineage differentiation during breast tumorigenesis. Developmental biology, 463(1), 77–87. https://doi.org/10.1016/j.ydbio.2020.04.007

Disciplines

Medical Education | Medicine and Health Sciences

PubMedID

32376245

Department(s)

USF-LVHN SELECT Program, USF-LVHN SELECT Program Students

Document Type

Article