MARGINALIA
By Any Other Name
By giving tumors their right names, scientists gain power over them
Robert L. Dorit
Pity taxonomy. When it is not being mistaken for the craft of making
dead things look alive, the science of naming things seems, in this
age of scientific razzle-dazzle, hopelessly old-fashioned.
And yet the act of naming is, in many ways, the fundamental task of
our intellect. The world, as William James suggested, appears
"a blooming, buzzing confusion." As scientists, our
ability to parse that confusion—to group objects into
meaningful categories and give those categories names—is both
the prerequisite to and the culmination of our understanding of the
world. The way we name things, however, inevitably affects how we
perceive those things.
Nowhere is the importance of naming more obvious than in the ways we
describe breast cancer, a disease that evokes faint anxiety every
time its name is uttered. Descriptions of this disease go back 3,000
years; over the past 30 years, it has become one of the most
intensively studied diseases, not to mention the focus of
promotional and educational campaigns. Yet despite this long history
and our relentless scrutiny, we are not yet sure what "breast
cancer" is, or even whether it is a single disease. The more we
learn of this condition and its underlying mechanisms, the more
complex and multifaceted this disease appears: We are making
progress in our understanding of this disease, but sometimes the
very name impedes us.
Identity Crisis
So what makes breast cancer "breast cancer"? Part of the
answer surely is, to borrow the realtor's mantra, location,
location, location. Breast cancer describes tumors that, in both men
and women, occur in breast tissue. But is that enough to give all
tumors of the breast the same name? Their occurrence in the same
part of the body may indeed reflect a deeper underlying similarity,
a lifelong and irreversible identity shaped by the neighborhood in
which the tumor cells grew up. But location could instead be a
superficial similarity—an address that groups together
unrelated conditions and obscures connections to tumors in other
parts of the body. And the riddle deepens.
The progenitor cell of a breast tumor may have once been a
well-defined cell in the lining of a milk duct. At that point, the
progenitor cell would have been keenly aware of its location in
space, of its age, of its identity and responsibilities as a duct
cell. But cells that begin to grow uncontrollably, as they do in a
tumor, lose their bearings, shun their roots and even appear to move
back in time, undoing the process of differentiation that made them
what they are. A pathologist scrutinizing cells from a biopsy looks
for those cells that have lost their way, that have forgotten what
they are. So what are we to call these tumor cells that are
in the breast but no longer of the breast?
Perhaps the answer consists in not being fooled by looks, but
instead in attending to some prominent feature of cellular behavior.
Yet behavior, too, may be misleading. Much of the biology and
epidemiology of breast cancer can be understood by focusing on the
interaction between breast tumors and a single circulating hormone:
estrogen. Estrogen is a powerful message for cells, prompting those
who heed it to divide. The increased risk of breast cancer
associated with obesity in post-menopausal women reflects the
ability of fat tissue to produce estrogen, increasing a woman's
lifetime exposure to estrogen. The protective effect of early
childbearing and extended breastfeeding on breast cancer risk stems
from the suppression of ovulation and the consequent reduction in
lifetime estrogen exposure. Even one of the best bits of recent news
in this field, the eight percent decline in breast cancer incidence
seen in the United States in 2003, is connected to the decline in
hormone-replacement therapy (which includes estrogen) as a treatment
for menopausal symptoms. Given all of this, surely estrogen
sensitivity is the hallmark of breast cancer, the one empirical
feature that unites all breast tumors?
Surprisingly, no. A third of breast tumors turn out to be deaf to
estrogen, having lost the ability to make and position estrogen
receptors (ERs) on the surfaces of their cells. These ER-negative
tumors may not be able to hear the command of estrogen to divide,
but unfortunately they miss the meaning of declining estrogen
levels: stop dividing. As a result, these tumors are more dangerous
than their attuned counterparts—faster spreading, harder to
treat, more likely to recur. Based on functional criteria,
ER-negative tumors may well deserve their own separate name. By the
same token, many ovarian tumors are keenly sensitive to levels of
circulating estrogen, accounting for the frequent co-occurrence of
ovarian and breast tumors in certain patient populations. Do all
estrogen-responsive tumors deserve their own label too, regardless
of what piece of human real estate they despoil?
Molecular Choir
In the end, our ability to name diseases properly may depend on our
getting to know them better, or on looking beneath surface
appearances for deeper understanding. Virtually every human cell
carries within it the entire human genome, 30,000 different
instructions for the manufacture of 100,000 proteins. At any point
in space and time, some instructions must be sung out loud, others
left silent. The identity, location and function of every cell in
our body depend on the correct interpretation and interplay of those
musical fragments. At this scale, healthy cell behavior depends on a
well-rehearsed and synchronized molecular chorus. Conversely, every
genetic disease reflects a rogue element in the choir, a disturbance
in the careful interpretation of biological information. Cancer is
no exception.
We have known for a century that cancer must involve a deep
disturbance in the mechanisms that regulate cell growth, cell
division and cell identity. But until recently, we were not in a
position to ask intimate questions of the 30,000 molecular singers
on the cellular stage: Who is singing off-key? Who is coming in too
soon or too late? Now, thanks to technology developed in conjunction
with the Human Genome Project, we can look at what each gene is
doing in the cell at any point in time. More precisely, we can look
at how loudly each of the 30,000 genetic instructions is being sung
at any point in time. With this technology, we can also ask the
question we have been hinting at from the outset: Are all breast
cancers the same and hence deserving of the same name?
At the genomic scale, every breast cancer examined shows a large
subset of genes being read differently than they would be in normal
breast cells. Some genes are read too loudly
("overexpressed"), others too quietly
("underexpressed"), and it is the noise of these
undisciplined molecular voices that results in breast tumors. But
are all breast tumors reading the same, albeit incorrect, score? The
answer is an unequivocal no, which perhaps should not surprise us. A
condition that is characterized by a malfunction of the delicate
processes that regulate cell growth and division is not likely to
result from the same, single cause in every case.
The tragic reality of our lives is that there will always be many
more ways of screwing things up than there will be of getting them
right, and this axiom holds true of biological systems as well.
Breast cancer turns out to be a heterogeneous collection of
molecular miscues. Hidden beneath the apparent similarity of all
breast cancers lie many corrupt musical scores. What once seemed to
us a single illness with a similar set of underlying causes has been
transformed into multiple discordant conditions. Choruses of genes
that carry the tune in normal cells blare in certain breast tumors
but only whisper in others. What seemed simple suddenly appears
hopelessly complicated.
Variations and a Theme
Yet hopelessly complicated is not the same as chaotic. As more and
more breast tumors are scrutinized at this level of detail, new
patterns have emerged. Our worst fear—that every tumor would
be unique, precluding an overall understanding of breast
tumors—has not been realized. There are ways of grouping
breast tumors based on the study of their molecular voices, and the
resulting number of tumor classes, in the range of 5 to 10, has
remained manageable. But what is most important is not that each
class of breast cancer deserves its own name. What matters is that
these detailed portraits of breast tumors have profound implications
for diagnosis and treatment. These categories provide starting
points for the development of specific therapies tailored to newly
revealed types of "breast cancer." These classes respond
differently to chemotherapy and to radiation. They have different
probabilities of recurrence, remission and metastasis.
Distinguishing them is hardly hair-splitting; these differences
matter to all involved.
We are witnessing a radical shift in our approach to illness: away
from symptoms and toward diagnoses based on cause and mechanism. For
many complex diseases, the perception of one monolithic condition
with a single name based on symptoms will likely give way to more
nuanced, mechanism-based nomenclatures. What we call an illness is
not just a matter of semantics. Everything—diagnosis,
treatment, research, funding and ultimately prevention and
cure—rides on getting the name right.