Alexander D. Borowsky, MD
Dr. Borowsky is a Surgical Pathologist with expertise in Diagnostic Breast Pathology. His research training includes characterization of transgenic mouse models of prostate cancer and the molecular analysis of a fusion oncogene central to the pathogenesis of MALT lymphoma.
Among the population of neoplastic cells in human breast cancers, only a small minority - perhaps as few as one in 1000 - appear to be capable of forming new malignant tumors. Existing therapies are designed to kill as many cells within the tumor as possible, but it may be that these “cancer stem cells” are the critical target. This “cancer stem cell hypothesis” explains some of the clinical features unique to breast cancer progression (compared to other cancers, colon cancer for example). New technology has helped to identify these cells for the fist time, and opens the door to ask critical questions about what makes them tick.
We have developed a mouse model of mammary pre-cancer that precisely matches the properties of human breast pre-cancer (ductal carcinoma in situor DCIS). Several unexpected findings have lead to the hypothesis that we have isolated a functional pre-cancer stem tissue, harboring individual pre-cancer stem cells, and that these cells have a prescribed behavior that does not depend on additional influences. In other words, the pre-cancer stem cells we have discovered are pre-programmed to become cancers, at a specific time (latency) and with a specific behavior (metastatic or non-metastatic.) Can we identify and isolate these cells? What is their origin, and how are they programmed? Can they be re-programmed?
Identification of cancer stem cells in human breast cancers is a new technology. Finding these cells at the earliest possible timepoint in cancer or pre-cancer progression promises new insight on the earliest events leading to breast cancer. The model system we have developed is uniquely suited to finding these early cells. The combination of time-honored techniques of mouse mammary gland transplantation with new techniques for identifying cells with “stem cell” behavior is the innovative element. While there is some risk that these cells will not be accessible, preliminary evidence suggests that they can be isolated. This will provide evidence to support hypotheses of breast cancer initiation and progression mechanisms.
A number of prostate cancer models in mice have been generated. A recurring theme in these models is the frequent generation of large in situ lesions, but the rare occurrence of invasive adenocarcinoma. Understanding of the molecular pathways activated or disrupted in various genetically engineered mice and correlating this with the careful examination of the phenotypes that result, will lead to new hypotheses of oncogenesis. Sometimes these hypotheses can be tested using cross breeding of genetically engineered mice. Additional genetically engineered mice will be generated “from scratch” when necessary. The current interest of the laboratory is to further investigate a handful of potential tumor suppressor genes that are found to be down regulated in high throughput expression analysis studies. One example of this is Nes1, which appears to be down regulated by methylation early in Breast and Prostate Cancer. A strategy to create a tissue targeted (conditional) knockout of this gene is underway in the laboratory.
With the recent explosion of gene expression profiles, including work at the UC Davis Cancer Center, there is a growing need for validation and translation of these data into sorting out clinically and biologically relevant findings. New ways of employing these findings in clinical practice are necessary. Traditionally Northern blot analysis is used to validate microarray findings. However, this requires relatively pure cell populations which are uncommon in human disease. The Borowsky lab uses the Laser Capture Microdissector (LCM) instrument coupled with real time quantitative PCR to evaluate gene expression levels in specific cell populations in human tissues and tumors.
Hsia EY, Kalashnikova EV, Revenko AS, Zou JX, Borowsky AD, Chen HW. Deregulated E2F and the AAA+ coregulator ANCCA drive proto-oncogene ACTR/A1B1 overexpression in breast cancer. Mol Cancer Res. 2010 Feb;8(2):183-93.
Cardiff RD, Borowsky AD. Precancer: sequentially acquired or predetermined? Toxicol Pathol. 2010;38(1):171-9.
Workman HC, Miller JK, Ingalla EQ, Kaur RP, Yamamoto DI, Beckett LA, Young LJ, Cardiff RD, Borowsky AD, Carraway KL, Sweeney C, Carraway KL 3rd. The membrane mucin MUC4 is elevated in breast tumor lymph node metastases relative to matched primary tumors and confers aggressive properties to breast cancer cells. Breast Cancer Res. 2009;11(5):R70.
Bowen SL, Wu Y, Chaudhari AJ, Fu L, Packard NJ, Burkett GW, Yang K, Lindfors KK, Shelton DK, Hagge R, Borowsky AD, Martinez SR, Qi J, Boone JM, Cherry SR, Badawi RD. Initial characterization of a dedicated breast PET/CT scanner during human imaging. J Nucl Med. 2009 Sep;50(9):140-8.
Choi MS, Catana AM, Wu J, Kim YS, Yoon SJ, Borowsky AD, Gambhir SS, Gupta S, Zern MA. Use of bioluminescent imaging to assay the transplantation of immortalized human fetal hepatocytes into mice. Cell Transplant. 2008;17(8):899-909.
Miller JK, Shattuck DL, Ingalla EQ, Yen L, Borowsky AD, Young LJ, Cardiff RD, Carraway KL 3rd, Sweeney C Suppression of the negative regulator LRIG1 contributes to ErbB2 overexpression in breast cancer. Cancer Res. 2008 Oct 15;68(20):8286-94.
Damonte P, Gregg JP, Borowsky AD, Keister B, Cardiff RD. EMT tumorigeneis in the mouse mammary gland. Lab Investigation. 2007 Dec; 87(12):1218-26..
Borowsky AD. Special considerations in mouse models of breast cancer. Breast Diseases. Breast Dis. 2006-2007;28:29-38.
Farrington-Rock C, Kirilova V, Dillard-Telm L, Borowsky AD, Chalk S, Rock MJ, Cohn DH, Krakow D. Disruption of the Flnb gene in mice phenocopies the human disease spondylocarpotarsal synostosis syndrome. Hum Mol Genet. 2007 Jul 17
Namba R, Maglione JE, Davis RR, Baron CA, Liu S, Carmack CE, Young LJ, Borowsky AD, Cardiff RD, Gregg JP. Heterogeneity of mammary lesions represent molecular differences. BMC Cancer. 2006 Dec 5;6:275.
Yen L, Cao Z, Wu X, Ingalla ER, Baron C, Young LJ, Gregg JP, Cardiff RD, Borowsky AD, Sweeney C, Carraway KL 3rd. Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor cell growth. Cancer Res. 2006 Dec 1;66(23):11279-86.
Oskouian B, Sooriyakumaran P, Borowsky AD, Crans A, Dillard-Telm L, Tam YY, Bandhuvula P, Saba JD. Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer. Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17384-9. Epub 2006 Nov 7.
Borowsky AD, Dingley KH, Ubick E, Turteltaub KW, Cardiff RD, Devere-White R. Inflammation and atrophy precede prostatic neoplasia in a PhIP-induced rat model. Neoplasia. 2006 Sep;8(9):708-15.
Derossi C, Bode L, Eklund EA, Zhang F, Davis JA, Westphal V, Wang L, Borowsky AD, Freeze HH. Ablation of mouse phosphomannose isomerase (Mpi) causes mannose-6-phosphate accumulation, toxicity, and embryonic lethality. J Biol Chem. 2005 Dec 8.
Namba R, Young LJ, Maglione JE, McGoldrick ET, Liu S, Wurz GT, Degregorio MW, Borowsky AD, Macleod CL, Cardiff RD, Gregg JP. Selective estrogen receptor modulators inhibit growth and progression of premalignant lesions in a mouse model of ductal carcinoma in situ. Breast Cancer Res. 2005 Sep 13;7(6):R881-R889.
Chao RC, Pyzel U, Fridlyand J, Kuo YM, Teel L, Haaga J, Borowsky A, Horvai A, Kogan SC, Bonifas J, Huey B, Jacks TE, Albertson DG, Shannon KM. Therapy-induced malignant neoplasms in Nf1 mutant mice. Cancer Cell. 2005 Oct;8(4):337-48.
Borowsky AD, Namba R, Young LJT, Hunter KW, Hodgson JG, Tepper CG, McGoldrick ET, Muller WJ, Cardiff RD, Gregg JP. Syngeneic mouse mammary carcinoma cell lines: Two closely related cell lines with divergent metastatic behavior. Clinical & Experimental Metastasis 2005 22(1): 4758.
Maglione JE, McGoldrick ET, Young LJ, Namba R, Gregg JP, Liu L, Moghanaki D, Ellies LG, Borowsky AD, Cardiff RD, MacLeod CL. Polyomavirus middle T-induced mammary intraepithelial neoplasia outgrowths: single origin, divergent evolution, and multiple outcomes. Molecular Cancer Therapy, 3(8):941-953, 2004.
Borowsky AD, Munn RJ, Galvez JJ, Cardiff RD, Ward JM, Morse HC 3rd, Kogan SC, Aldape KD, Louis DN, Bosenberg MW. Mouse models of human cancers (Part 3). Comparative Medicine, 54(3):258-270, 2004.
UC Davis Mouse Biology Program
UC Davis Cancer Center
Regional Interviewer Vanderbilt University School of Medicine Admissions Committee
Fellow of the College of American Pathology
Fellow of the United States and Canadian Academy of Pathology