Genes Determining Estrogen Susceptibility in Breast Cancer

Institution: Stanford University
Investigator(s): Wensheng Wei, Ph.D. -
Award Cycle: 2000 (Cycle VI) Grant #: 6FB-0106 Award: $86,400
Award Type: Postdoctoral Fellowship
Research Priorities
Etiology and Prevention>Etiology: the role of environment and lifestyle



Initial Award Abstract (2000)
Although breast cancer is one of the most extensively studied human malignant neoplasmcancers, the genetic bases of its origin and progression are still in their initial stages of understanding. It is widely accepted that the effects of estrogens on the growth of breast epithelium influence breast cancer risk. Endocrine therapy is an important clinical treatment for breast cancer since certain breast cancer cells are sensitive to endocrine drugs. However, while many non-metastatic breast tumors are initially estrogen dependent (and thus responsive to endocrine drugs) many they eventually experience progression to an estrogen-independent (and metastatic) form and become drug resistant. The alterations of cancer cells in their response to drugs and hormones are poorly understood. Therefore, the identification of genes and genetic pathways implicated in breast cancer estrogen response is likely to further the quest for improved diagnostic markers and provide targets for therapies aimed at preventing or impeding the spread of breast malignancies.

Therefore, the identification of genes and genetic pathways implicated in breast cancer estrogen response is likely to further the quest for improved diagnostic markers and provide targets for therapies aimed at preventing or impeding the spread of breast malignancies.

The proposed project will employ a novel genetic procedure that was recently developed in my mentor Dr. Stanley N. Cohenís laboratory. This approach allows the identification of previously unknown genes that plays a crucial roles in control of breast cancer cells in response to hormone and drug treatment.

The overall goal of the proposed research is the identification, isolation and characterization of genes (estrogen susceptibility genes, ESGs) that are required for the normal function or expression of estrogen receptors in response to estrogen treatment of breast cancer.


Final Report (2002)
Steroid hormones play a central role in mammalian development by regulating the expression of a variety of genes. Estrogens are particularly responsible for the development of female secondary sex characteristics and are known to have a profound effect on the proliferation of estrogen responsive tissues. Importantly, estrogens enhance the proliferation of some breast cancers. Certain breast cancer cells are sensitive to endocrine drugs. Unfortunately, all patients with advanced breast cancer eventually experience progression to drug resistance. The alterations of cancer cells in their response to drugs and hormones are poorly understood.

The overall goal of this project is the identification, isolation, and characterization of genes that are required for the normal function of estrogen receptor (ER) in response to estrogen treatment of human breast cancers (estrogen susceptibility genes, ESGs). In addition to ESGs involved in estrogen-dependence and antiestrogen-susceptibility of breast cells, genes and genetic pathways regulated by these ESGs will be studied as well. Random homozygous knock-out (RHKO) strategy is used as the major experimental approach in this project.

The RHKO strategy is a novel and seemingly powerful method in terms of its ability of randomly inactivating both alleles of chromosomal genes within cell populations. However, problems were encountered during my study on a parallel project (study of human metastasis suppressor genes, MSGs) that was initiated prior to this project. I have been spending much of the research time and effort to improve the methodology to be used. Specifically, the following strategic changes have been made during the course of this project: 1) employment of Lenti-virus-based delivery system to increase the infection titer in making RHKO library; 2) correction of the bi-directional activity of the CMV-TRE antisense promoter in RHKO gene search vector; 3) employment of an alternative EST-RHKO strategy.

Besides the methodology improvement, conditions under which I used to screen for ESGs have been established. A RHKO library was constructed on MCF-7 human breast cancer cell line. The library screening was carried out. Currently, much of the effort has been put on increasing the library size and drug screening. The continuation of the project in the future will be focused on the identification and characterization of the genes isolated from this screening.

Breast cancer affects one out of eight women during their lifetime, and it is the second leading cause of cancer-related deaths among women in the United States. Although breast cancer is one of the most extensively studied human malignant neoplasm, the genetic bases of its origin and progression are still in their initial stages of understanding. The identification of genes and genetic pathways implicated in the breast cancer estrogen response is likely to further the quest for improved diagnostic markers and provide targets for therapies aimed at preventing or impeding the spread of breast malignancies.