Early events in breast carcinogenesis

Keywords: breast cancer, aging, senescence, stress, pre-malignancy, genomic instability 

My laboratory focuses on understanding molecular alterations that occur early during carcinogenesis. In particular, we are interested in the basic question of how epithelial cells integrate the myriad extrinsic and intrinsic forms of cellular stress and how abrogation of a proper stress response drives early carcinogenesis. Normal cells initiate stress pathways in response to cellular insults from genotoxic, oxidative, metabolic or mitogenic signals. If these insults induce a level of genomic damage above an internal threshold, an apoptotic (cell death) or senescent (irreversible cell arrest) program limits the propagation of these damaged cells. In vitro data have established that these programs are important surveillance mechanisms that protect cells from cellular transformation. In principle, these failsafe mechanisms may provide efficient barriers to carcinogenesis in vivo.

Pre-malignant breast disease represents a heterogeneous group of lesions that are not all associated with the development of subsequent invasive breast cancer. We have recently reported that epithelial cells within pre-malignant breast lesions that demonstrate markers of senescence and maintain an intact response to cellular stress identify women that are less likely to develop subsequent tumor events. In contrast, pre-malignant epithelial cells that have bypassed this barrier and have an aberrant response to cellular stress identify women at increased risk of developing subsequent invasive disease. The presence of molecular phenotypes that can be assayed prior to the development of invasive breast carcinoma suggests cells with these characteristics pre-exist and therefore serve as markers of risk.

The laboratory is continuing to develop novel in vitro models from primary human mammary epithelial cell cultures that recapitulate the morphologic and molecular heterogeneity of pre-malignant disease. Through high throughput molecular profiling, functional genomic screens and in situ analysis of clinical samples, these models will provide fundamental insights into molecular alterations that are initiated in pre-malignancy and how they may be linked to established oncogenic events that define malignancy. These efforts will also contribute biomarkers for risk assessment and potential therapeutic targets for intervention.

Graduate Student(s):

• Rania Chenhade
• Noor Salman

Selected Publications:

Link to Pubmed Publications

• Gauthier ML, Berman HK, Miller CJ, Chew KL, Moore D, Rabban J, Chen YY, Kerlikowske K, Tlsty TD. 2007. Abrogated response to cellular stress identifies DCIS associated with subsequent tumor events and defines basal-like breast tumors. Cancer Cell. 12:479-491.

• Bean GR, Bryson AD, Goldenberg V, Pilie, PG, Baker JC, Brander, DMU, Case, NR, Gauthier M, Reynolds, PA, Troch MM, Dong M, Scott V, Wilke LG, Yee L, Kimler BF, Fabian CJ, Zalles CM, Broadwater G, Tlsty TD, Seewaldt VL. 2007. Morphologically Normal-Appearing Mammary Epithelial Cells Obtained from High-Risk Women Exhibit Methylation Silencing of p16(INK4a). Clinical Cancer Res. 15:6834-41.

• Zhang J., Pickering C, Holst CR, Gauthier ML, Tlsty TD. 2006. p16INK4a modulates p53 in primary human mammary epithelial cells. Cancer Research. 66:10325-10331.

• Berman H, Zhang J, Crawford YG, Gauthier ML, Fordyce CA, McDermott KM, Sigaroudinia M, Kozakiewicz K, Tlsty TD. 2005. Genetic and epigenetic changes in mammary epithelial cells identify a subpopulation of cells involved in early carcinogenesis. Cold Spring Harb Symp Quant Biol.70:317-27.

• Gauthier ML, Pickering CR, Miller CJ, Chew KL, Fordyce CA, Berman HK, Tlsty TD. 2005. p38 regulates COX-2 in human mammary epithelial cells and is activated in pre-malignant tissue. Cancer Research. 65:1793:1799.

• Tlsty TD, Crawford YG, Holst CR, Fordyce CA, Zhang J, McDermott K, Kozakiewicz K, Gauthier ML. 2004. Genetic and epigenetic changes in mammary epithelial cells may mimic early events in carcinogenesis. J.Mammary Gland Biol. Neoplasia 9:263-274.

• Crawford Y, Gauthier ML, Joubel A, Mantei K, Afshari CA, Tlsty TD. 2004. Histologically normal human mammary epithelia with silenced p16INK4A overexpress COX-2, promoting a malignant program. Cancer Cell 5:263-273.

• Shim V, Gauthier ML, Sudilovsky, D, Mantei K, Chew K, Moore D, Cha I, Tlsty TD, Esserman L. 2003. COX-2 expression is related to nuclear grade in DCIS and is increased in its normal adjacent epithelium. Cancer Research. 63:2347-2350.