The Role of Clim Proteins in Breast Cancer

Institution: University of California, Irvine
Investigator(s): Suman Verma, Ph.D. -
Award Cycle: 2010 (Cycle 16) Grant #: 16FB-0028 Award: $37,961
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Biology of the Normal Breast: the starting point



Initial Award Abstract (2010)

The heterogeneous nature of breast tumors has been linked to the stem cell origination of this disease. Cofactors of LIM (Clims) proteins are proteins that facilitate selective gene expression in various cell types. They have been implicated in breast cancer, because they are over-expressed in many breast tumors, and are associated with other transcription factors that can cause breast cancer. We also found that they are highly expressed in normal stem cells, both in hair follicles and mammary gland. Furthermore, we demonstrated that Clims are involved in the maintenance of hair follicle stem cells, leading us to hypothesize that Clims might also be involved in the homeostasis of mammary epithelial stem cells and have a possible role in breast cancer initiation.

To study the role of Clims in mammary biology and breast cancer in more detail, we have two aims in this project:
#1: To investigate the cellular role of Clims in regulation of mammary epithelial stem cell homeostasis. This includes changes in stem cell self-renewal, differentiation into mature epithelial cells, and apoptosis (programmed cell death).
#2: To investigate the role of Clims in breast tumor formation and progression using a xenograft model (i.e., human breast cancer cells grown in mice) of breast tumor development.

Using a mouse model developed in our lab for the inhibition of Clims activity, as well as normal human mammary stem cells deficient in Clims activity, we will elucidate the role of Clims in proliferation, differentiation and survival of normal breast stem cells. We will also explore Clims in mouse model of breast tumor development. These studies, performed in mouse and human stem cells, and cancer cells will provide a better understanding of Clims in normal and breast cancer stem cell regulation how this is associated with breast cancer development.

These studies could identify a novel drug target affecting the self-renewal and/or differentiation of normal and cancer stem cells, thus potentially decreasing sensitivity to breast carcinogens and increasing sensitivity to chemotherapeutic agents.




Final Report (2011)

Note: the PI resigned this grant after 8 months to pursue other career opportunities.

Breast cancer is a heterogeneous disease at molecular and cellular level. This heterogeneity and diversity of the disease has been one of the reasons that we have not been able to eradicate this disease so far. Stem cells are the cells that have ability to self-renew and differentiate in to many different types of cells in the body. It has been evident that cancer cells originate from normal stem cells. But, in the normal stem cells the ability to self-renew and differentiate is highly regulated and controlled, while it is de-regulated in cancer cells. If we can understand the pathways by which normal stem cells regulate their ability to self-renew and differentiate then we will be able to better understand the de-regulations in cancer cells that cause them to self-renew infinitely.

Clim are the proteins that enhance the transcription of genes involved in myriad of processes highly relevant to cancer such as proliferation and differentiation .They have been suggested to have a role in breast cancer as they are over-expressed in many breast tumors and are also over-expressed in locations of normal stem cells such as hair follicle and mammary gland. Furthermore, we demonstrated that Clims are involved in the maintenance of hair follicle stem cells, leading us to hypothesize that Clims might also be involved in the homeostasis of mammary epithelial stem cells and have a possible role in breast cancer initiation.

n the original application, we showed that the mice expressing inactive form of Clims have reduced number of normal mammary stem/progenitor cells, indicating that Clims are required for their maintenance. In the period of funding we have done functional assays to confirm these results. We have found that mammary cells isolated from mice expressing inactive form of Clim have reduced number and size of mammospheres (i.e., usually hollow “balls” of cells representing the stem cell population) in comparison to wild type mice, indicating lesser number of stem cells in these mice. We have further confirmed these results by knocking down Clim proteins in normal breast cell models.

In summary, in this period of funding we have been able to establish that Clim proteins are required for the maintenance of normal mammary stem cells.