Journal Article

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

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

2022

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 1-Phosphatidylinositol 3-kinase / Adenoviruses / Animals / Basal-like / Biomedical and Life Sciences / Biomedicine / Brca1 / BRCA1 protein / BRCA1 Protein - genetics / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Cancer / Cancer Research / Chemotherapy / Cre recombinase / Cyclin-dependent kinase 4 / Epithelium / Epithelium - metabolism / ErbB-2 protein / Estrogens / Female / Females / Gene expression / Genes / Genetic engineering / Genetically modified organisms / Hormones / Humans / Laboratory animals / Mammary gland / Mammary Glands, Human - metabolism / Mammary Neoplasms, Animal - pathology / Mice / Molecular modelling / Mouse model / Mutation / Oncology / Oncology, Experimental / Phosphatidylinositol 3-Kinases / Proteins / RNA sequencing / Rodents / Scientific equipment and supplies industry / Surgical Oncology / Translation / Trp53 / Tumors / Western blotting