The most common events in breast cancer (BC) involve chromosome arm losses and gains. Here we describe identification of 1089 gene-centric common insertion sites (gCIS) from transposon-based screens in 8 mouse models of BC. Some gCIS are driver-specific, others driver non-specific, and still others associated with tumor histology. Processes affected by driver-specific and histology-specific mutations include well-known cancer pathways. Driver non-specific gCIS target the Mediator complex, Ca++ signaling, Cyclin D turnover, RNA-metabolism among other processes. Most gCIS show single allele disruption and many map to genomic regions showing high-frequency hemizygous loss in human BC. Two gCIS, Nf1 and Trps1, show synthetic haploinsufficient tumor suppressor activity. Many gCIS act on the same pathway responsible for tumor initiation, thereby selecting and sculpting just enough and just right signaling. These data highlight ~1000 genes with predicted conditional haploinsufficient tumor suppressor function and the potential to promote chromosome arm loss in BC.
Bibliographical noteFunding Information:
We would like to thank Ramesh Shrivdasani, Joshua J. Paré, Ben Alman, Freddy Radtke, Tak Mak, Tim Lane, and Doug Melton for mutant and/or transgenic mice. The Egan lab acknowledges grant support from the Canadian Breast Cancer Foundation/Canadian Cancer Society Research Institute, the CDMRP/US Army Department of Defence, The Joint Canada-Israel Health Research Program with funding from the Canada’s International Development Research Centre and the Canadian Institutes of Health Research. S.E.E., M.D.T., E.Z., and J.R.W. acknowledge funding from the Terry Fox Foundation. J.R. acknowledges funding from the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant (#RGPIN-2016-06485). We acknowledge technical assistance and/or advice from Idil Temel, Toshi Kawamata, Judah Glogauer, Natalia M. Ruiz Agamez, Ruth G. Wong, Jack Plumaj, Nayasta A. Kusdaya, Alessandro C. Manno, Christine E.B. Jo, Jesse Joynt, Rameen Beroukhim, Lothar Hennighausen, Christine Watson, Robert Callahan, Robert Cardiff, Thomas Nalpathamkalam, Bhooma Thir-uvahindrapuram, Jerid Robinson, and Liz Li. Finally, we wish to thank Life Science Editors (https://www.lifescienceeditors.com/), who assisted with writing and presentation of these results. We gratefully acknowledge Ben Pakuts for illustrations as shown in Fig. 9.
© 2021, The Author(s).