Before she decided to study biology and genetics as an undergraduate at the University of Virginia in the late 1970’s, Jane Fountain seriously considered becoming a fine art painter or an architect.
These days Fountain, an assistant professor of biochemistry and molecular biology, doesn’t wield a paint brush or pour over renderings.
Yet through her genetic research laboratory at the USC Norris Comprehensive Cancer Center, she is painting an ever-clearer picture of the tumor suppressor genes whose breakdown is responsible for melanoma, one of the deadliest cancers because it metastasizes, or spreads, so quickly.
In fact, Fountain’s goal is to create a genetic blueprint for melanoma progression, which would help not only in identifying better diagnostic markers for the disease but might lead, eventually, to the development of better treatments for melanoma.
Tumor suppressor genes are one of two types of genes important in regulating tumor growth. Tumor suppressor genes in normal cells essentially prevent development of malignancy by acting as guards against cell proliferation When tumor suppressor genes are deleted or mutated, the cells are able to grow more rapidly.
The other type of gene is an oncogene, which promotes abnormal uncontrolled cell growth. Current theory holds that both the growth enhancement of oncogenes and the unrestrained growth allowed by altered tumor suppressor genes play a part in cancer development.
Three years after establishing her lab at USC, the 36-year-old scientist finally feels confident that she has identified a tumor suppressor gene that’s a primary target in both sporadic and familial (inherited) melanoma. It’s the p16 gene on chromosome 9, an area of intense scrutiny in much genetic cancer research. Fountain said her soon-to-be-published paper will be the first to prove definitively that this gene is a primary target in sporadic melanoma.
“I’m really meticulous, which is a good thing and a bad thing,” laughed the outgoing Wilmington, Delaware, native. “When we publish our results, we’re really confident of them, though we may not always be lucky enough to be first to the punch.”
As a positional cloner, or someone who identifies a region of the genome containing a critical tumor suppressor gene, Fountain maintains such attention to detail is important.
Fountain pointed out that she often uses a more labor-intensive technique, known as southern blotting, for discerning deletions of the p16 gene. Others have used more rapid means, such as PCR-based genetic mapping, which can be difficult to interpret due to the amplification of normal contaminating DNA in tumor samples. As a result, “With p16 there’s been a lot of bad data that’s been produced and published, just in the flurry of getting the papers out and establishing turf.”
Fountain acknowledged that she picked melanoma in part because it was easier to establish that turf. In the late 1980’s, when she began her postdoctoral fellowship in the laboratory of David Housman at the Massachusetts Institute of Technology, “there were few geneticists working on melanoma, maybe about five groups in the world that were taking genetic approaches to look at melanoma.”
Still, her main interest was in the disease’s rapid metastasis.
“I wanted to work on the most metastatic disease, because I thought if you could figure out metastasis and stop that, then you’ve won.”
These days Fountain acknowledges that that was a rather “naive” approach, and points out that even before she began her research, tumor progression was acknowledged to be multiple gene inactivations. As a result, her melanoma research is branching out to include parts of other chromosomes, including chromosomes 6 and 11.
On chromosome 11, Fountain is collaborating with another lab that focuses on functional assays: where pieces of chromosome 11 are re-introduced into melanoma cell lines that are then injected into mice. The presence of a normal copy of a “melanoma” tumor suppressor gene should inhibit tumor formation in these mice.
By monitoring which regions of chromosome 11 suppress tumor formation versus which regions do not, Fountain and her lab are rapidly narrowing down a candidate region on chromosome 11.
The functional assays, in this particular case, have proved more valuable than the molecular ones in succinctly localizing a tumor suppressor gene on this chromosome.
Fountain thinks functional assays are the wave of the future in identifying tumor suppressor genes.
“It’s going to become more and more difficult using molecular means alone to identify tumor suppressor genes,” she said. “The most obvious ones have been identified; the ones lost at the highest frequency in tumors. Now we’re looking at the ones not lost at the highest frequency, or that may be deleterious after just loss of one copy. Technically they’re going to be more difficult to identify.”