Biology subjects

Lofgren, K. A.

Publications and source records attributed to Lofgren, K. A..

4 recordsLinked to original sources

bioRxiv2023

Grb7 knockout mice develop normally but litters born to knockout females fail to thrive

Growth factor receptor-bound 7 (Grb7) is an adaptor protein involved in signal transduction downstream of multiple receptor tyrosine kinases, including ERBB, FGFR and PDGFR pathways. Experimental studies have implicated Grb7 in regulating cell proliferation, survival, migration and invasion through its large repertoire of protein-protein interactions. Here, we describe the generation and characterization of a Grb7 knockout mouse. These mice are viable and fertile. A lacZ knock-in reporter was used to visualize Grb7 promoter activity patterns in adult tissues, indicating widespread Grb7 expression in glandular epithelium, the central nervous system and other tissues. The sole defect observed in these animals was a failure of Grb7 knockout females to successfully raise pups to weaning age, a phenotype that was independent of both paternal and pup genotypes. These data suggest a regulatory role for Grb7 in mammary lactational physiology.

developmental biology↗

bioRxiv2023

Mammary-specific ectopic expression of mutant human GATA3 did not potentiate medroxyprogesterone acetate-driven mouse mammary tumorigenesis

GATA3 is somatically mutated in approximately 15% of estrogen receptor positive human breast tumors, however the mechanism(s) by which these alterations contribute to tumorigenesis are unclear. The observed patterns of mutations suggest a strong selective pressure to mutate a single allele of GATA3 in a manner favoring retention of the first of two zinc finger domains. The non-mutated GATA3 allele is maintained and expressed. We and others have hypothesized that expression of the mutant GATA3 protein may actively contribute to breast tumorigenesis, however the aging of several independently generated mouse models with mammary-specific mutant GATA3 expression did not result in tumorigenesis. In this study, we evaluated whether a mammary tumor-promoting dose of medroxyprogesterone acetate could synergize with mammary specific mutant GATA3 (G335fs) expression and accelerate the kinetics of tumor formation. We report that the tumor incidence rate in these animals did not differ from that observed in wild-type littermate controls.

cancer biology↗

bioRxiv2022

Pan-cancer distribution of cleaved cell-surface Amphiregulin, the target of the GMF-1A3 antibody drug conjugate

Amphiregulin (AREG) is a transmembrane protein which, following TACE/ADAM17-dependent cleavage, releases a soluble Epidermal Growth Factor Receptor ligand domain that promotes proliferation of normal and malignant cells. Expression of Amphiregulin has been described by immunohistochemistry in several tumor types, including lung, prostate, head and neck, gastric, pancreatic and breast cancers but evidence for a functional requirement for Amphiregulin in these malignancies is more limited. We have previously described the development of a monoclonal antibody, GMF-1A3, that selectively recognizes the Amphiregulin epitope that is revealed following cleavage by TACE/ADAM17 and demonstrated that drug conjugates of this antibody have anti-tumor activity in mouse models. By directly evaluating Amphiregulin cleavage, immunohistochemistry on tissue specimens using this antibody can be used to evaluate the extent to which Amphiregulin is being proteolytically processed in cancer, which is a more direct measure of Amphiregulin activity. As a potential companion diagnostic for this antibody-drug conjugate, this immunohistochemistry assay allows identification of tumors with high levels of the cleaved Amphiregulin target. Here we evaluate levels of cleaved Amphiregulin in 370 specimens from 10 tumor types and demonstrate that it is widely expressed in solid tumors and is especially common (more than 50% of cases) in breast, prostate, liver and lung cancer.

cancer biology↗

bioRxiv2021

Anti-tumor efficacy of an MMAE conjugated antibody targeting cell surface TACE/ADAM17-cleaved Amphiregulin in breast cancer

The Epidermal Growth Factor Receptor ligand, Amphiregulin, is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. Amphiregulin is a single-pass transmembrane protein proteolytically processed by TACE/ADAM17 to release the soluble EGFR ligand, leaving a residual transmembrane stalk that is subsequently internalized. Here, we report the development of an antibody drug conjugate, GMF-1A3-MMAE, targeting an AREG neo-epitope revealed following ADAM17-mediated cleavage. The antibody does not interact with uncleaved Amphiregulin, providing a novel means of targeting cells with high rates of Amphiregulin shedding. Using fluorescent dye conjugation, we demonstrated that the antibody is internalized by cancer cells in a manner dependent on the presence of cell surface cleaved Amphiregulin. Antibodies conjugated with monomethyl auristatin E (MMAE) were cytotoxic in vitro and induced rapid regression of established breast tumor xenografts in immunocompromised mice. We further demonstrate that these antibodies recognize the Amphiregulin neo-epitope in formalin fixed paraffin embedded tumor tissue, suggesting their utility as a companion diagnostic for patient selection.

cancer biology↗