BUFFALO, NY — Newly published research from Roswell Park Cancer Institute (RPCI) describes, for the first time, how the tumor-suppressing functions of the protein p53 become weakened by a hormone receptor in breast cancer cells and mammary stem cells. According to principal investigator Gokul M. Das, PhD, Co- Director of the Breast Disease Site Research Group at RPCI, the culprit is estrogen receptor (ER).
Stem cells are non-specialized cells that have the capacity to self-renew and to differentiate into more mature cells. These cells, under abnormal conditions, can give rise to cancer cells. “Stem cells in cancer act like seeds of weeds,” explains Dr. Das. “Just as regular mowing of a lawn does not kill the weeds, existing cancer drugs are ineffective against cancer stem cells. Tumor suppressor p53 keeps the stem cells from going awry.”
Dr. Das and his colleagues found that ER, a docking site for the hormone estrogen in cells, binds to p53 and blocks its ability to regulate the genes responsible for tumor growth. “In stem cells, ER strangles p53 and prevents it from executing its tumor-suppressor functions. ER promotes abnormal cell production in two ways: it turns on genes that support cell proliferation and turns off genes that inhibit cell production and are, under normal circumstances, turned on by p53,” explains the researcher.
While preliminary, this research may shed light on the driving forces underlying breast cancer, which in turn could lead to the development of more effective therapeutic strategies.
The paper also reports on studies analyzing response to tamoxifen therapy in breast cancer patients. Data suggest that the presence of normal p53 is an important determinant of positive therapeutic response; a prospective clinical trial on breast cancer patients based on these observations is underway at RPCI.
“The goal of this research is to effectively identify which breast cancer patients are most likely to respond to anti-estrogen hormonal therapy drugs, such as tamoxifen,” notes Dr. Das, who is also Associate Professor in the Department of Pharmacology and Therapeutics at RPCI.
The paper, “Mechanisms of Estrogen Receptor Antagonism Toward p53 and its Implications in Breast Cancer Therapeutic Response and Stem Cell Regulation,” is published online at the Proceedings of the National Academy of Sciences of the United States of America (PNAS) website as an Early Edition, and is available at http://www.pnas.org/papbyrecent.shtml. Investigators from Roswell Park Cancer Institute, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (Stuttgart, Germany), Eberhard Karls Universität Tübingen (Tübingen, Germany) and University of Cincinnati College of Medicine collaborated on this work.
The mission of Roswell Park Cancer Institute (RPCI) is to understand, prevent and cure cancer. RPCI, founded in 1898, was one of the first cancer centers in the country to be named a National Cancer Institutedesignated comprehensive cancer center and remains the only facility with this designation in Upstate New York. The Institute is a member of the prestigious National Comprehensive Cancer Network, an alliance of the nation’s leading cancer centers; maintains affiliate sites; and is a partner in national and international collaborative programs. For more information, visit RPCI’s website at http://www.roswellpark.org, call 1- 877-ASK-RPCI (1-877-275-7724) or email firstname.lastname@example.org.
Annie Deck-Miller, Senior Media Relations Manager