Targeted alterations of the ATX/LPA signaling axis in mice creates a tumorigenic environment from which mammary neoplasias can develop. Using mammary tumors derived from this model, we have established a transplantation procedure in which fragments of different tumors are orthotopically transplanted in syngeneic mice. Under these conditions, primary murine tumors displayed a wide spectrum of growth rates suggesting that alteration of ATX/LPA signaling axis engenders a variety of different breast cancer subtypes with distinctive propensity to progress, which is similarly observed in human neoplastic disease. Comprehensive analysis of high-throughput RNAseq and Reverse Phase Protein Array (RPPA) data revealed that despite being passaged multiple times, tumors retained their distinct growth profiles and also maintained surprisingly stable molecular characteristics. The remarkable consistency in terms of growth, transcriptional landscape, and protein expression demonstrates that in this model a small fragment randomly taken from any region of the tumor can accurately and reproducibly regenerate an entire developmental program when grown in vivo. It follows that each consistent molecular change detected in the tumor likely represents either a marker of the tumor or its mechanistic oncodriver. Using unbiased multidimensional scaling analysis of RNAseq data we have identified tumors that were strictly related to normal mammary tissue in terms of gene expression as well as individual gene signatures that differentiate slow- vs fast-growing tumors. Furthermore, we have identified several stable alterations at a protein level that are commonly found in human breast cancers including cMYC, BRCA2, PARP1, Claudin-7, Her3, and E-Cadherin. These results demonstrate that an orthotopic transplantation procedure in immunocompetent hosts represents a relevant preclinical platform to probe human breast cancer heterogeneity and pinpoint molecular alterations that are mechanistically responsible for malignant behavior.

Citation Format: Lorenzo Federico, Kang Jin Jeong, Dong Zhang, Zhenlin Ju, Zechen Chong, Jennifer B Dennison, Gordon B Mills. Studies on tumor heterogeneity using a preclinical model of breast cancer caused by genetic alteration of the ATX-LPA axis [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 P6-06-01.