Our laboratory has utilized a three-dimensional culture model to investigate the phenotypic effects of genes implicated in breast tumorigenesis on the biology of mammary epithelial cells. This model system has revealed interesting cell-biological behaviors that are not detectable in standard monolayer cultures and has provided important mechanistic insights into processes and pathways that appear to play important roles in tumor initiation and progression in the mammary gland (e.g, filling of the lumen, escape from growth arrest, loss of polarity, etc). In the studies proposed in this application, we will further expand the application of these models for studies of tumor pathogenesis by examining the fate of single mammary epithelial cells that carry genetic alterations associated with breast cancer initiation or progression (e.g. expression of oncogenes or downregulation of tumor suppresors). Since tumors evolve from clonal alterations in isolated, individual cells, rather than globally in all cells within such a tissue, the proposed experimental models will more closely mimic the natural events associated with spontaneous tumor initiation and progression, and allow us to examine the influence of normal cells and the architectural organization of mammary structures on expression of phenotypic changes provoked by oncogenic insults. We will use the well-characterized MCF-10A immortalized human mammary epithelial cell model as well as other in vitro and in vivo mammary epithelial cell models that we are currently developing. The studies will involve systematic comparisons of the fate of cells subjected to distinct oncogenic insults in proliferating versus growth-arrested structures, in single cells versus the total cell population, and in immortalized versus primary cell three- dimensional structures. Findings from the in vitro models will be evaluated in vivo using inducible expression of cDNAs or shRNAs in single cells within the mammary gland. These studies promise to provide important information on (i) the fate of cell clones carrying oncogenic alterations, (ii) the role of epithelial cells within the microenvironment on the outcome of oncogene insults, (iii) the mechanisms of escape from suppressive influences of the microenvironment, and (iv) requirements for conferring a competitive advantage to tumor cells within tissue-like structures.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Whitehead Institute for Biomedical Research
United States
Zip Code
Bailey, Shannon T; Westerling, Thomas; Brown, Myles (2015) Loss of estrogen-regulated microRNA expression increases HER2 signaling and is prognostic of poor outcome in luminal breast cancer. Cancer Res 75:436-45
Hines, William C; Su, Ying; Kuhn, Irene et al. (2014) Sorting out the FACS: a devil in the details. Cell Rep 6:779-81
Yamamoto, Shoji; Wu, Zhenhua; Russnes, Hege G et al. (2014) JARID1B is a luminal lineage-driving oncogene in breast cancer. Cancer Cell 25:762-77
Jeselsohn, Rinath; Yelensky, Roman; Buchwalter, Gilles et al. (2014) Emergence of constitutively active estrogen receptor-? mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res 20:1757-67
Lu, Haihui; Clauser, Karl R; Tam, Wai Leong et al. (2014) A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol 16:1105-17
Pathania, Shailja; Bade, Sangeeta; Le Guillou, Morwenna et al. (2014) BRCA1 haploinsufficiency for replication stress suppression in primary cells. Nat Commun 5:5496
Hu, Yiduo; Petit, Sarah A; Ficarro, Scott B et al. (2014) PARP1-driven poly-ADP-ribosylation regulates BRCA1 function in homologous recombination-mediated DNA repair. Cancer Discov 4:1430-47
McAllister, Sandra S; Weinberg, Robert A (2014) The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol 16:717-27
Hill, Sarah J; Rolland, Thomas; Adelmant, Guillaume et al. (2014) Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage. Genes Dev 28:1957-75
Hill, Sarah J; Clark, Allison P; Silver, Daniel P et al. (2014) BRCA1 pathway function in basal-like breast cancer cells. Mol Cell Biol 34:3828-42

Showing the most recent 10 out of 89 publications