Fatty Acid Synthase and Breast Cancer

Institution: The Burnham Institute for Medical Research
Investigator(s): Lynn Knowles, Ph.D. -
Award Cycle: 2002 (Cycle VIII) Grant #: 8FB-0107 Award: $86,400
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (2002)
Cancer is a complex disease that develops when cells loose the ability to control their rates of proliferation. Moreover, these cells have developed mechanisms that allow them to not only proliferate rapidly, but also to overcome signals that tell them to die. Over the past few years, It has become evident that fat is a key regulator of tumor cell growth. Unfortunately though, we have few hints as to how fat regulates tumor cells. Here, I have planned studies to determine how fat controls cell growth. Results from my work are likely to yield new strategies for treating breast cancer, both with drugs and by dietary alterations.

Orlistat is an FDA approved drug for treating obesity. My sponsor has discovered that orlistat has an unanticipated effect; it inhibits fat production by tumor cells. More importantly, orlistat is able to selectively kill tumor cells. Yet, we have no information on why orlistat has this effect. Thus, I plan to answer the following questions: I will be using standard cell biology and cellular biochemistry techniques. All of my work will be conducted in tumor cells in culture.

The proposed study has two innovative elements. First, I am studying a unique activity of orlistat, a drug approved for treating obesity. My sponsor’s laboratory has discovered that orlistat can selectively kill tumor cells. This gives us a new lead into approaches for drug design. The second aspect of my proposal is the way I plan to figure out how orlistat is working and to identify genes that are controlled by orlistat.

Final Report (2004)
Orlistat is an approved obesity drug that blocks fat production by inactivating the enzyme fatty acid synthase (FAS). We previously found that Orlistat blocks cell growth and induces programmed cell death in mammary tumor cells. We hypothesized that those effects were due to the blockade of FAS.

The major breakthrough during the final year of the fellowship was our discovery that the Orlistat effect is due to inhibition of FAS and not the result of alterations in other cellular targets. We determined this by using a novel technique called small interfering RNA (siRNA) which essentially knocked down the production of the FAS protein. This resulted in a suppression of tumor growth identical to that induced by Orlistat treatment. An important discovery was that Skp2 is a critical intermediate for regulating tumor growth suppression in response to FAS inhibition by Orlistat and FAS siRNA. However, Skp2 does not regulate programmed cell death induced by inhibition of FAS. We also found that the specific pathway leading to programmed cell death in response to Orlistat is an effect of FAS inhibition. The underlining mechanism for this is the focus of the ongoing study.

Overall, these data show that inhibiting fat production is an effective way to kill tumor cells or at least to block their growth.

Symposium Abstract (2003)
Over the past few years an enzyme called fatty acid synthase (FAS), has been implicated in tumor growth and progression. Fatty acid synthase is the only enzyme that can generate fats within the cell; all other fat comes from the diet. Our study is focused on understanding why fatty acid synthase is required for tumor growth, and attempts to develop novel inhibitors of this enzyme. We have made the surprising finding that orlistatTM, a drug approved by the FDA for treating obesity, can block the function of fatty acid synthase and prevent tumor cell growth. In many cases orlistat also promotes tumor cell death. We have begun to unravel the mechanism of each of these orlistat-induced events, believing that such information will provide a greater understanding of how to deploy FAS inhibitors against cancer. The present studies show that tumor cells have a unique “fatty acid checkpoint” that controls their ability to progress through the cell cycle and divide. The retinoblastoma pathway, known for its role in controlling cell cycle progression, plays an important part in mediating this block in cell division. It appears that a blockade of FAS activates the retinoblastoma checkpoint, keeping cells from dividing. The present studies also reveal that orlistat causes the activation of a set of enzymes in tumors called caspases, which are responsible for initiating programmed cell death. Collectively, these studies reveal that FAS controls both tumor cell proliferation, and can enact tumor cell death. Thus, FAS is a valid target for breast cancer therapy and compounds like orlistat are potential lead compounds for drug development.

Inhibition of fatty acid synthase induces caspase 8-mediated tumor cell apoptosis by Up-regulating DDIT4.
Periodical:Journal of Biological Chemistry
Index Medicus: J Biol Chem
Authors: Knowles LM, Yang C, Osterman A, Smith JW.
Yr: 2008 Vol: Oct. 2008 Nbr: Abs: Pg:ePub