THE GENETIC CONTROL OF BREAST CANCER METASTASIS

Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36688, USA
Abstract: is a complex event involving coordinated
cross-talk of several proteins. Genes that control the resultant metastasis
can be broadly classified as metastasis promoter genes (MPGs) and
metastasis suppressor genes (MSGs). There is an explosion of information
in the studies that focus on these genes; however, thus far, a very few of
them are actually tested clinically and/or in vivo functionally. In this
chapter we will focus on the metastasis controlling genes that have been
tested for clinical relevance or functional properties in breast cancer
metastasis models.
Keywords: metastasis suppressing genes (MSGs), functional validation, gene discovery
1. INTRODUCTION
Breast cancer is capable of having unusually long latency. It is also
capable of spreading at a variety of secondary sites that include vital
organs such as brain, lungs, and bones (1). Metastasis is the spread and
concomitant growth of the cancer at a discontinuous site. The chances of
survival from metastatic breast cancer are less than 5%. Thus effective
prevention and treatment of metastasis is a major focus of research in
breast cancer. Several cells are shed by the primary tumor in the circulation,
however only a subset of cells seems to form metastasis. There
are several models explaining the origin of metastasis. A unifying fact
that has emerged thus far is it is controlled by the genetic makeup of
control breast cancer metastasis, one can notice two distinct groups:
metastasis promoting genes (MPGs) and metastasis suppressor genes
(MSGs). MSGs suppress the spread and growth of the cancer at a
Rajeev S. Samant, Oystein Fodstad, and Lalita A. Shevde
the cancer cells (2, 3). In the published literature regarding genes that
R.E. Mansel et al. (eds.), , 7–30.
the human genome project and gene profiling studies has lead to a
substantial addition in the number of genes in these categories. However
in this chapter we discuss only the human genes that are tested in vivo
functionally (using animal models) or those that have been validated in
multiple controlled clinical studies.
Breast cancer is a term broadly applied to infiltrating ductal, infiltrating
lobular, medullary, tubular, and mucinous carcinomas. Despite improved
understanding of the molecular mechanisms of metastasis, the genetic
information available is not categorized to a definite subtype. Thus, there
still remains a gap between integrating the relevance of the findings and
a definite subtype/category. The experimental findings for one subtype
(or cell line) may not hold true for another subtype of breast cancer.
Hence, although a metastasis gene expression signature is identified, the
patient subpopulation that relates to these genes is not clear.
There are several key questions in the genetic control of breast
cancer.
1. What genetic changes are necessary and sufficient for cells to
become metastatic?
2. Are there global metastasis controlling genes?
3. Are metastases clonal?
4. Does the metastasis signature exist in primary tumor?
5. What controls the gene expression change with the onset of
metastasis?
6.
7. Are there specific genes that direct the metastasis to a specific
secondary site?
8. What are the host factors and secondary site microenvironment
that contribute to metastasis?
The answers to these questions will have a profound impact on the
diagnosis, prognosis, and treatment (therapeutic intervention) of breast
cancer.
2.
RELATED GENES
1970s but was advocated aggressively after a decade. Metastasis promoting
genes were identified as genes that promote breast tumor aggressiveness,
this included invasion and migration. However successful colonization at
the secondary site (that will lead to macroscopic metastasis) was only
8 Samant, Fodstad, and Shevde
Do the metastasis-associated genes have a normal physiologic role?
IDENTIFICATION OF METASTASISThe
concept of metastasis-associated genes was launched in the early
secondary site without altering tumor formation whereas MPGs do the
opposite (4–6). The phenomenal outburst of information concomitant to
There are several innovative tools and tricks used for the gene
identification.
The more traditional approach compared cell lines that differ in
metastatic potential using karyotyping to look for additions/
deletions/translocations. These techniques point to a locus or a
region on a chromosome that bears a metastasis-related gene.
However there is a very involved discovery process for the
identification of the exact gene.
A more recent approach is to monitor differential gene
expression using differential display or subtractive hybridization.
Contemporary methods involve the use of recently developed
microarray technologies. The success is limited due to the vast
amount of data obtained and false positives.
Also needless to say that differential gene expression is not the only
way to regulate gene function, posttranslational modifications such as
butions and these are apparent with the advent of modern proteomic
techniques.