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Breast Cancer Research
Published in: Breast Cancer Research 1/2022

Open Access 01-12-2022 | Breast Cancer | Research

Loss of Brca1 and Trp53 in adult mouse mammary ductal epithelium results in development of hormone receptor-positive or hormone receptor-negative tumors, depending on inactivation of Rb family proteins

Authors: Ludmila Szabova, Melanie B. Gordon, Lucy Lu, Nathan Pate, Laura Bassel, Anthony J. Iacovelli, Baktiar Karim, Philip J. Homan, Deborah B. Householder, Theresa M. Guerin, Sandra Burkett, Amanda M. Day, Wendi Custer, Zoe Weaver Ohler

Published in: Breast Cancer Research | Issue 1/2022

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Abstract

Background

Breast cancer is a heterogenous disease with several histological and molecular subtypes. Models that represent these subtypes are essential for translational research aimed at improving clinical strategy for targeted therapeutics.

Methods

Different combinations of genetic aberrations (Brca1 and Trp53 loss, and inhibition of proteins of the Rb family) were induced in the mammary gland by injection of adenovirus expressing Cre recombinase into the mammary ducts of adult genetically engineered mice. Mammary tumors with different genetic aberrations were classified into molecular subtypes based on expression of molecular markers and RNAseq analysis. In vitro potency assays and Western blots were used to examine their drug sensitivities.

Results

Induction of Brca1 and Trp53 loss in mammary ductal epithelium resulted in development of basal-like hormone receptor (HR)-negative mammary tumors. Inhibition of Rb and Trp53 loss or the combination of Rb, Trp53 and Brca1 aberrations resulted in development of luminal ductal carcinoma positive for ER, PR, and Her2 expression. HR positivity in tumors with Rb, Trp53 and Brca1 aberrations indicated that functionality of the Rb pathway rather than Brca1 status affected HR status in these models. Mammary tumor gene expression profiles recapitulated human basal-like or luminal B breast cancer signatures, but HR-positive luminal cancer models were endocrine resistant and exhibited upregulation of PI3K signaling and sensitivity to this pathway inhibition. Furthermore, both tumor subtypes were resistant to CDK4/6 inhibition.

Conclusions

Examination of molecular expression profiles and drug sensitivities of tumors indicate that these breast cancer models can be utilized as a translational platform for evaluation of targeted combinations to improve chemotherapeutic response in patients that no longer respond to hormone therapy or that are resistant to CDK4/6 inhibition.
Appendix
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Metadata
Title
Loss of Brca1 and Trp53 in adult mouse mammary ductal epithelium results in development of hormone receptor-positive or hormone receptor-negative tumors, depending on inactivation of Rb family proteins
Authors
Ludmila Szabova
Melanie B. Gordon
Lucy Lu
Nathan Pate
Laura Bassel
Anthony J. Iacovelli
Baktiar Karim
Philip J. Homan
Deborah B. Householder
Theresa M. Guerin
Sandra Burkett
Amanda M. Day
Wendi Custer
Zoe Weaver Ohler
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2022
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-022-01566-4

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