My specific aims are to examine the role of cancer stem cells and their niche microenvironment in malignant progression of subtypes of human breast premalignancy, ductal carcinoma in situ (DCIS). The objectives are to test whether premalignant cell lines, SUM225,, and subtypes of human DCIS contain distinct cancer stem cell subpopulations which exhibit unique cancer stem cell properties of increased self-renewal potential, quiescence, and tumorigenicity. My strategy is to use fluorescent activated cell sorting (FACS) and known surface markers to isolate stem/progenitor and differentiated subpopulations and to examine their cancer stem cell properties which include, 1) in vitro self-renewal and differentiation potential by standard mammosphere assay and colony formation in Matrigel, respectively, 2) in vivo long term and short term self-renewal by using a novel strategy of xenotransplantation into humanized stroma of mice fat pads, 3) tumorigenicity by growth rate and potential to form invasive lesions, and 4) quiescence by long term label retaining studies. Furthermore, the role of endothelial cells in establishing a cancer stem cell niche microenvironment will be examined by in vitro co-culture and in vivo co-transplantation studies. My rationale is that cancer stem cells and normal tissue stem cells express similar surface markers by which they may be identified and characterized. Once cancer stem cells are identified, efforts will be aimed at defining their unique gene profiles. These studies will provide a basis for discovery of molecular targets for risk assessment, prevention of recurrence, and malignant progression tailored to subtypes of DCIS. My long term career goal is to lead a research group focused towards prevention of human breast cancer malignant progression in a translational research environment. I served as an academic and clinical pharmacologist for seven years before obtaining a Ph.D. and post-doctoral training in basic sciences in cellular signaling and mouse mammary gland stem cell biology. The Career Development Award is an excellent opportunity to gain additional experience in research in human breast cancer in collaboration with the Breast Cancer Center at Baylor College of Medicine. Baylor College of Medicine houses exceptional research centers and facilities and provides an ample opportunity for scientific collaboration, and education. Relevance: Breast pre-cancer lesions may contain a rare population of cancer stem cells. Cancer stem cells may be unique to different types of pre-cancer lesions and may explain why some patients will experience recurrences or develop invasive cancers while others do not. My goal is to examine the role of cancer stem cells in invasive progression of subtypes of pre-cancer lesions and to develop individualized strategies for risk assessment and prevention of invasive breast cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Transition Award (R00)
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Special Emphasis Panel (ZCA1-RTRB-2 (J1))
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Mohla, Suresh
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University of Kansas
Schools of Medicine
Kansas City
United States
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Kittrell, Frances; Valdez, Kelli; Elsarraj, Hanan et al. (2016) Mouse Mammary Intraductal (MIND) Method for Transplantation of Patient Derived Primary DCIS Cells and Cell Lines. Bio Protoc 6:
Scribner, K C; Behbod, F; Porter, W W (2013) Regulation of DCIS to invasive breast cancer progression by Singleminded-2s (SIM2s). Oncogene 32:2631-9
Elsarraj, Hanan S; Hong, Yan; Valdez, Kelli et al. (2013) A novel role of microRNA146b in promoting mammary alveolar progenitor cell maintenance. J Cell Sci 126:2446-58
Li, Hui; Duhachek-Muggy, Sara; Qi, Yue et al. (2012) An essential role of metalloprotease-disintegrin ADAM12 in triple-negative breast cancer. Breast Cancer Res Treat 135:759-69
Kittrell, Frances S; Carletti, Martha Z; Kerbawy, Sofia et al. (2011) Prospective isolation and characterization of committed and multipotent progenitors from immortalized mouse mammary epithelial cells with morphogenic potential. Breast Cancer Res 13:R41
Valdez, Kelli Elizabeth; Fan, Fang; Smith, William et al. (2011) Human primary ductal carcinoma in situ (DCIS) subtype-specific pathology is preserved in a mouse intraductal (MIND) xenograft model. J Pathol 225:565-73
Pal, Arindam; Valdez, Kelli E; Carletti, Martha Z et al. (2010) Targeting the perpetrator: breast cancer stem cell therapeutics. Curr Drug Targets 11:1147-56
Bussard, Karen M; Boulanger, Corinne A; Kittrell, Frances S et al. (2010) Immortalized, pre-malignant epithelial cell populations contain long-lived, label-retaining cells that asymmetrically divide and retain their template DNA. Breast Cancer Res 12:R86
LaMarca, Heather L; Visbal, Adriana P; Creighton, Chad J et al. (2010) CCAAT/enhancer binding protein beta regulates stem cell activity and specifies luminal cell fate in the mammary gland. Stem Cells 28:535-44
Behbod, Fariba; Kittrell, Frances S; LaMarca, Heather et al. (2009) An intraductal human-in-mouse transplantation model mimics the subtypes of ductal carcinoma in situ. Breast Cancer Res 11:R66