Abstract P4-08-03: Demonstration of the evolutionary dynamics of the progression from breast hyperplasia to cancer using the duct epithelial agent based model (DEABM)
Authors: Chapa Joaquin , An Gary , Kulkarni Swati A 
Published: May 2015

Introduction: Abnormal proliferation in the breast is clinically seen ranging from hyperplasia to atypia to in situ carcinomas (DCIS) to invasive cancers. Whether these states comprise points along an evolutionary continuum is a subject of debate, but has significant implications for prevention, prognosis, and treatment. Due to the length of time involved, tumor evolution is difficult to study in vivo and in vitro models. We hypothesize a continuum from hyperplasia to cancer can be demonstrated by examining patterns of accumulated mutations in tumors. We employ a previously developed computational model of ductal epithelial dynamics, the DEABM (1), to simulate and track accumulated mutations during the progression from a normal epithelial population through hyperplastic states to the development of invasive tumors

Methods: Simulation experiments were performed using an expanded DEABM, which incorporates the functions of luminal and myoepithelial cells, their progenitors and fibroblasts. DNA damage can potentially disrupt 12 functional pathways regulated by oncogenes and tumor suppressors implicated in breast cancer (BRCA1, P53, E-cadherin, RUNX3, Myc, ER, TGF-b, MMP-3, EGFR, HER-2 and Telomerase). The expanded DEABM allows for sequential tracking of genetic lesions in each cell. 3,000 simulations in both wild-type (WT) and BRCA1-mutated states were run over 40 years of simulated menses. Cell populations were characterized as normal, hyperplastic or malignant based on quantitative cell expansion from baseline, as well as by mutational profiles, sequential order of mutations and ER status.

Results: Tumor profiles approximated epidemiologic rates of cancer incidence and ER/HER2 status. 2.6 % of WT developed malignancy vs. 45.9% of BRCA1. WT tumors were 54% ER+/HER2-, 17% ER+/HER2+, 6% ER-/HER2+ and 22% ER-/HER2-. BRCA1 tumors were 29% ER+/HER2-, 7% ER+/HER2+, 13% ER-/HER2+ and 50% ER-/HER2-. Hyperplastic populations carried more mutations than non-hyperplastic populations (p&gt;.01) and were more likely to carry mutations in telomerase, E-cadherin and genes related to ER expression (TGFB, RUNX3, p&lt;.01), similar to the early mutations found in ER+ tumors (RUNX3, TGFB, telomerase p&lt;.01). Early P53 mutations were common in all tumors (p&lt;.01). ER- tumors were more likely to carry early mutations in BRCA1, MYC and genes associated with epithelial-mesenchymal transition (MMP-3, p&lt;.01). ER- tumors carried significantly more mutations than ER+ (p&lt;.01), corresponding to data on increased genomic instability in ER- and BRCA1-associated tumors.

Conclusion: The DEABM generates diverse tumors that express tumor markers consistent with epidemiologic data. The DEABM also generates non-invasive, hyperplastic populations, analogous to atypia and/or DCIS, via mutations to genes known to be present in hyperplastic lesions and early mutations in breast cancers. The results demonstrate that agent-based models are well-suited to studying tumor evolution through stages of carcinogenesis and have the potential to be used to develop prevention and treatment strategies.

Ref: Chapa J, et al. "Examining the Pathogenesis of Breast Cancer Using a Novel Agent-Based Model of Mammary Ductal Epithelium Dynamics." PloS one 8.5 (2013).

Citation Format: Joaquin Chapa, Gary An, Swati A Kulkarni. Demonstration of the evolutionary dynamics of the progression from breast hyperplasia to cancer using the duct epithelial agent based model (DEABM) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-08-03.