Breast Cancer Research
A major goal of the Breast Center is to eliminate breast cancer as a disease of public health proportions. In order to make further progress we need to have a better understanding of the environmental influences, as well as the genes which contribute to breast cancer development and aggressiveness. A better understanding of the molecular pathways controlling important cellular events, such as cell survival, cell proliferation, differentiation and apoptosis is also crucial. Finally, the role of supporting tissues in the tumor, such as stromal components, myoepithelium, and angiogenesis is important. To increase our knowledge of the biology of breast cancer, the Center has established a research agenda that covers a broad array of important research areas.
Normal mammary gland development
An understanding of factors which regulate growth and development of normal
breast cells could provide important clues to better understanding the causes
of breast cancer.
Biology of premalignant breast disease
We know that breast cancer evolves through a series of stages of increasingly
abnormal breast ductal cells. Understanding the biological and molecular alterations
underlying premalignant disease could lead to new strategies to prevent cancers
from forming and new diagnostic markers useful to physicians.
Genetics of premalignant disease
Identification of a panel of molecular alterations contributing to breast
cancer development could lead to genetic markers that will predict which women
are most likely to acquire breast cancer in their lifetimes. These women could
then be targeted for breast cancer prevention.
Prevention
Methods to block the effects of estrogen have been shown to be effective in
preventing some breast cancers. Studies are underway to block alternative
molecular pathways that are also important in growth regulation, differentiation
and cell death, as additional means of prevention.
Oncogenes and suppressor genes
Identification of the genes that when over expressed (oncogenes) or lost (tumor
suppressor genes) lead to breast cancer could provide important clues to the
causes of breast cancer as well as new treatment and prevention strategies.
Growth regulation by polypeptide growth factors
The female hormone, estrogen, a steroid hormone, is crucial for breast cancer
development and progression, but other factors are also important. Polypeptide
growth factors that mediate their effects through membrane receptors contribute
important proliferative and cell survival signals that could also be potential
targets for diagnosis and treatment. Understanding how these factors function
and how they cooperate with estrogen signaling pathways is an important research
area.
Transcriptional regulation
The expression of genes and their encoded proteins that regulate important
cellular effects is controlled by a complex process involving a panoply of
transcription factors. A better understanding of these very basic cellular
events in breast cancer could also provide important diagnostic and treatment
targets.
Structure and function of estrogen receptor (ERα and ERβ)
Estrogen is a major contributor to the development of breast cancer. This
hormone mediates its effects by binding to nuclear receptors, of which there
are now at least two known types, ERα and ERβ. These important transcription
factors regulate the growth of breast cancer, and their activities are modulated
by a large number of other receptor-interacting proteins that can activate
or repress function. A basic understanding of these pathways could lead to
new methods of prevention or treatment and a better understanding of how tumors
become resistant to treatments designed to block estrogen's effects.
Mechanisms of hormonal resistance
Drugs, such as tamoxifen, designed to block estrogen's effects or treatments
designed to lower the estrogen levels in patients are effective treatment
modalities, but many tumors eventually develop resistance. A better understanding
of the molecular events in this resistance could lead to markers of resistance
and to the development of new drugs to overcome or prevent resistance.
Selective estrogen receptor modulators (SERMs)
Tamoxifen was the first SERM used in breast cancer treatment and prevention,
but resistance develops in many patients and tamoxifen has some side effects.
The development of other, similar drugs, known as selective estrogen receptor
modulators, that are either more potent and or less toxic, is an important
research area. Faslodex, a SERM with more potent antiestrogenic qualities,
was developed in preclinical studies in the Center. Phase III clinical trials
in patients now are showing it to be among the most effective treatments available.
Angiogenesis in breast cancer
Breast cancer, like other cancers, relies on the development of new blood
vessels to support tumor growth. Preliminary data suggests that by inhibiting
this process some tumors can be effectively treated. A better understanding
of angiogenesis at the molecular level could have a profound impact for the
development of new treatment strategies. Preliminary data also suggests that
factors regulating angiogenesis may contribute to tamoxifen resistance.
Metastasis
The ability of some breast cancers to metastasize to other sites in the body
accounts for breast cancer mortality. However, not all patients have such
metastases and studies of this process could lead to ways of preventing the
metastatic phenotype or new techniques for predicting which patients are likely
to have metastases at diagnosis. Accurate identification of these patients
would be very important to clinicians, since only patients with metastases
would need systemic chemotherapy or hormonal therapy after surgery.
Prognostic and predictive biomarkers
Breast cancers are very heterogeneous in their aggressiveness and treatment
response. These differences among patients can be accounted for by the particular
set of genetic alterations in an individual patient's tumor. Identification
of each tumor's molecular fingerprint, then, could help to segregate patients
who have particularly aggressive tumors or who need to be treated with specific
therapies. A major goal of Breast Center research is to translate the information
learned in the laboratory about the genetic alterations in breast cancer and,
then, develop clinically useful assays, or molecular profile, to help clinicians
make treatment decisions. Faculty in the Breast Center have already contributed
much of the seminal information on assays that are currently used in patients,
such as estrogen and progesterone receptors, the HER-2 oncogene and proliferation
markers. Now, with the ability to investigate thousands of genes on an individual
tumor using microarray technology, more complete molecular profiling of a
patient's tumor is possible.