Scientists at the National Cancer Institute have been able to genetically manipulate human breast cancer cells into becoming independent of the female hormone estrogen, which initially regulated their growth.
The ultimate usefulness of this accomplishment in combating this cancer -- which strikes 110,000 American women every year and kills 40,000 -- may lie principally in the research direction it points to, rather than in any immediate clinical application.
It may lead to a new approach to treating breast cancer. Instead of trying to kill the cancer cells directly, the researchers will try to inactivate the chemicals that stimulate the growth of cancer.
Earlier research had demonstrated that breast cancer cells produce growth factors that not only stimulate the growth of the cancer cell, but "in a nasty way" stimulate the growth of neighboring normal cells needed to form tumors, says Dr. Marc Lippman, chief of the cancer institute's medical breast cancer section and one of the authors of the report in the current issue of Science.
Lippman notes that scientists also have learned that "99 percent of breast cancers require female sex steroids somewhere in their lifetime, but by the time they become metastatic, with tumor deposits growing throughout the body, only one third . . . are hormone-dependent."
Lippman uses the analogy of a faucet "dripping the growth factors" that make the cancer grow. Initially, when the cancer is "hormone-dependent," the faucet is regulated by estrogen. But by the time most of the breast cancers spread, they have escaped estrogen regulation "and the faucet has become locked in the on position," continuously producing the growth hormones, Lippman says.
The most recent research, described in the Science article, involved the use of test-tube breast cancer cells that started out hormone-dependent. By inserting into the cells' genetic makeup a known cancer-causing gene -- an oncogene -- and then injecting the cells into a mouse, the scientists found "that these breast cancer cells which had previously required estrogen in order to form tumors now were able to form them in a hormone-independent fashion."
"This is a nice trick," says Lippman. But it is "absolutely without interest" unless it explains how the breast cancer escapes hormonal control.
Lippman, who this weekend received the American Federation for Clinical Research's Young Investigator Award for his ongoing breast cancer research, says scientists have had evidence for almost a century that hormones were linked to breast cancer. New epidemiological studies seem to confirm the link.
For example, he notes that:
* "Women with no functioning ovaries have only a 1 percent chance of getting breast cancer." Most estrogen comes from the ovaries.
* "It has been known for many years that if you alter the hormone production of women with breast cancers -- by removing the ovaries or prescribing an anti-estrogen drug such as tamoxifen, some tumors would respond." (But, unfortunately, he notes, only about one third of the women respond, and of this third, only half would respond a second time and even fewer a third time.)
* "A woman having a baby at age 15 or 16 has one third the risk for breast cancer as a woman who never has a baby. And when you have a first baby after age 30, the risk of breast cancer goes up."
* "It is now appreciated that the age at which a woman starts to have menstrual periods is critical: A woman with periods before age 12, which is about the median age in the U.S., has about three times the risk of breast cancer as a woman whose periods start around age 16."
As the evidence linking hormones to the genesis of breast cancer continues to mount, more and more researchers, says Lippman, have been interested in finding ways of "altering the endocrine environment" to reduce the chances of developing breast cancer. To do this, some researchers are investigating the possibility of inducing false pregnancies in adolescent girls, or of using drugs to delay puberty by three or four years. These drugs "are available," says Lippman, "but whether or not this is safe to do is completely conjectural."
However, the NCI work, up to and including the currently published article and some subsequent findings, are pointing to an exciting alternative.
Because the breast cancers have been able to escape the regulation by estrogen, the anti-estrogen drugs used by clinicians, at some point, cease to affect the ravaging cancer.
However, Lippman's work suggests a new hypothesis -- and he emphasizes that it is "only" a hypothesis -- that the breast cancer cells "learn how to secrete the same growth factors without requiring estrogen to open the tap.
"Now this is a very exciting possibility," says Lippman, "because if this were to be true, then the same growth factors would be stimulating both hormone dependent and hormone-independent breast cancers, with the only difference being how they came to be secreted -- in one case regulated by estrogens and in the other case no longer needing estrogens.
"What that would mean," Lippman says, "is that a strategy directed against these growth factors might -- and I emphasize might -- be expected to be successful against both hormone-dependent and hormone-independent breast cancers because they are both dependent upon the same growth factors."
Lippman adds that what is not in the Science article "is that the cells that we made hormone-independent by introducing the oncogene known as the v-ras gene are now producing increased quantities of these same growth factors that used to be under estrogen regulation." It's as if Lippman taught the cancer cells to lock open the faucet which permits the growth factors to pour out.
Whether the faucet is turned on and off by estrogen or locked on without the need for any more estrogen, the growth factors appear to be the same.
Although, says Lippman, cancers are "normally very clever" in sidestepping ways clinicians devise to stop their growth, the breast cancer genes may "have been moderately stupid to secrete the very growth factors that they need in order to survive."
This makes them vulnerable, he believes, and specifically vulnerable "to something that might interact with the growth factors like a sponge, and sop them up to prevent them from working."
This "something," Lippman and his team believe, could be antibodies specifically aimed either at the growth factors themselves or at receptors on the cells which they affect. Receptors are the places on the cells where the growth factors attach themselves to stimulate the cell into abnormal activity.
Unlike most normal cells, says Lippman, cancer cells must either continue to grow or die. Most normal cells stop growing after they have accomplished their purpose. But when cancer cells are blocked from dividing, they can no longer exist. So whether or not the antibodies actually zapped the cancer cells or merely kept them from dividing, they could have a lethal effect.
"We are interested in and attempting to make such antibodies," says Lippman. "We know nothing about them with respect to whether they do or do not work, or they might be very toxic, conceivably, but it is an exciting idea.