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BCRL Home » History of the Breast Cancer Research Laboratory » The BCRL at the Fox Chase Cancer Center from 1991 to the present

The BCRL at the Fox Chase Cancer Center from 1991 to the present

Next: Transformation of HBEC with chemical carcinogens »

In 1991, Dr. Russo was appointed Chairman of the Department of Pathology in the Medical Division at Fox Chase Cancer Center, located in the Northeast section of Philadelphia. Most members of the original BCRL also made the move to Philadelphia in order to continue their line of research.

Capitalizing on the seminal studies performed in Michigan, the BCRL developed an in-vitro system for testing the transforming abilities of different genotoxic agents (Cancer Res 50: 6087, 1990; Carcinogenesis 14: 483, 1993). This has been an active area of research in this group, of which the ongoing goal has been to identify which genes are responsible for the expression of immortalization and transformation phenotypes (Cell Growth Different 1; 407, 1990; Mol Carcinogen 4:25, 1991, and 9; 46, 1994; Int J Oncol 6: 977,1995).

In Vitro system of cell transformation

At Fox Chase, the BCRL developed an in vitro experimental system to study the transformation of human breast epithelial cells (HBEC) with chemical carcinogens. Those studies led to the conclusion that in order to induce full neoplastic transformation, (i.e., expression of advantageous growth, anchorage independence, enhanced chemo-invasiveness, absence of ductulogenesis, and tumorigenesis in a heterologous host), the cells need to be immortalized prior to carcinogen exposure. The lab’s in vitro model of cell transformation was developed utilizing the immortalized HBEC MCF-10A transfected with c-Ha-ras oncogene, and MCF-10F treated with the carcinogen benzo(a)pyrene (BP).

Transformation of HBEC with c-Ha-ras oncogene

MCF-10A (Figure 12: Click to see), which was derived without viral or chemical intervention from mortal diploid human breast epithelial cells (HBEC) with an extended life span, has enabled tests to determine whether the insertion of an activated Ha-ras oncogene alone is capable of inducing malignant transformation in breast epithelium. MCF-10A cells were transfected with the c-Ha-ras oncogene contained in the plasmid pHo6-Tras. Their growth pattern on plastic, ability to grow tri-dimensionally in collagen, the expression of anchorage-independent growth, and independence from hormones and growth factors for proliferation, and tumorigenicity in nude mice were then tested and compared with those of MCF-10A parent cells, or cells transfected with the neomycin-resistant gene alone or with the proto-oncogene (pHo6neo) (Figure 12: Click to see).

Among the phenotypic markers indicative of in vitro cell transformation, the ability of cells to grow in an anchorage-independent manner is a reliable criterion (Figure 12: Click to see) especially when accompanied by tumorigenicity, since many normal cells are able to grow in methocel or agar but are unable to produce tumors. In MCF-10-neoT cells, however, this property was detected early, after the third passage post transfection, and was associated with tumorigenicity in nude mice, a phenomenon also expressed by breast tumor cell lines such as MDA-MB-231, BT-20, and MCF-7.

Next: Transformation of HBEC with chemical carcinogens »