Genetic Dissection of Cancer Development, Therapy Response, and Resistance in Mouse Models of Breast Cancer

Abstract

The cancer genomics revolution has rapidly expanded the inventory of somatic mutations characterizing human malignancies, highlighting a previously underappreciated extent of molecular variability between and within patients. Also in breast cancer, the most commonly diagnosed malignancy in women, this heterogeneity complicates the understanding of the stepwise sequence of pathogenic events and the design of effective and long-lasting target therapies. To disentangle this complexity and pinpoint which molecular perturbations are crucial to hijack the cellular machinery and lead to tumorigenesis and drug resistance, functional studies are needed in model systems that faithfully and comprehensively recapitulate all the salient aspects of their cognate human counterparts. Mouse models of breast cancer have been instrumental for the study of tumor initiation and drug response but also involve cost and time limitations that represent serious bottlenecks in translational research. To keep pace with the overwhelming amount of hypotheses that warrant in vivo testing, continuous refinement of current breast cancer models and implementation of new technologies is crucial. In this review, we summarize the current state of the art in modeling human breast cancer in mice, and we put forward our vision for future developments.

Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality

“…Nevertheless, secondary BRCA1/2 mutations explain only some of the cases of PARPi resistance (Ang et al, 2013). The requirement of BRCA1 for HR activity can be bypassed by the loss of the 53BP1-RIF1-REV7 pathway, as shown by various studies (Annunziato et al, 2016). In contrast, there is no evidence that HR can be rescued in the absence of BRCA2, suggesting that BRCA2-deficient tumors employ distinct, HR-independent pathways to overcome PARPi toxicity.…”

“…Drug resistance often follows the introduction of therapeutics in the clinic, and unfortunately PARPi are no exception (Audeh et al, 2010;Fong et al, 2009). Using cell lines and mouse models, several mechanisms of PARPi resistance have been identified, including upregulation of the P-glycoprotein (P-gp; also known as ABCB1) drug efflux transporter (Evers et al, 2008;Rottenberg et al, 2008) and restoration of HR activity (reviewed in Annunziato et al, 2016). While the clinical significance of P-gp-driven resistance remains controversial, HR restoration has been observed in human tumors that re-established BRCA1/2 function (Edwards et al, 2008;Swisher et al, 2008).…”

State of the art of overcoming efflux transporter mediated multidrug resistance of breast cancer

“…Several breast cancer mouse models for preclinical intervention trials such as genetically engineered mouse models (PDX models, organoids, non-germline models) have been established to investigate the progression of breast cancer and drug resistance mechanisms. In particular genetically engineered mouse models have been used ( 38 - 40 ). The hereditary breast cancer K14cre; Brca1 F/F ; p53 F/F mouse model of spontaneous breast tumors shows that doxorubicin and docetaxel resistance was associated with up-regulation of the two P-gp or thologs in mouse Mdr1a and Mdr1b.…”

“…Therefore, we can conclude that breast cancer MDR is related to expression of P-gp and ABCG2 in in vivo studies, and the combination of inhibitors and chemotherapeutic drugs can overcome MDR and increase the sensitivity of tumor tissue to drugs in vivo . Furthermore, the use of mouse models may help clinicians to derive real-time genotype-specific drug response profiles and design more effective and durable patient-specific regimens ( 38 , 40 ). Although MDR1 acts a potential resistance mechanism in breast cancer of mice, the role of MDR1 in mediating resistance has not been as clearly implicated in human breast cancer ( 45 ).…”

A synthetic lethal dependency on casein kinase 2 in response to replication-perturbing drugs in RB1-deficient ovarian and breast cancer cells

“…Maintenance therapy with PARP inhibitors extends the progression-free survival of patients with BRCA mutant tumors 4,5 . However, despite the initial success of the stratified approach, patients in this "better prognosis" cohort still often develop resistance to both chemotherapy and PARP inhibitors [6][7][8] , leading to disease relapses. This urges the development of strategies to improve therapeutic responses in HGSOC and TNBC patients.…”