Exploring Drug Resistance in Estrogen Receptor-positive Breast Cancer

Gokul Das, PhD

Tamoxifen is approved for the treatment of women diagnosed with certain types of early and advanced stage breast cancer. However, a large number of these women do not respond to the drug or develop a resistance to it. Several plausible reasons for such resistance have been suggested; however, the mechanisms remain largely unclear.  Research in Dr. Gokul Das’s laboratory revealed that estrogen receptor (ER) binds to a major tumor suppressor called p53 and inactivates it.  Tamoxifen prevents this strangling of the tumor suppressor by estrogen receptor thereby maintaining the anti-tumor activity of p53 in breast cancer cells. 

Based on these observations, Dr. Das’s lab has initiated a National Cancer Institute-funded clinical trial at RPCI in breast cancer patients to investigate the effect of short-term (4 weeks) pre-surgical Tamoxifen treatment on ER-p53 interaction in breast tumors.  We are actively recruiting patients to this clinical trial. However, as the patients undergo surgery immediately after the 4-week Tamoxifen treatment in this ongoing clinical trial (as delayed surgery to prolong Tamoxifen treatment is unethical), we are unable to address the effect of long-term effect of Tamoxifen therapy on disrupting ER-binding to p53 and on tumor growth. 

The new project supported by a grant from the Alliance Foundation will overcome this problem by transplanting a piece of the surgically removed patient breast tumor tissue in a lab model (technically called ‘xenograft’) and analyzing the long-term effects of Tamoxifen therapy and basis for tumor resistance to this therapy.  We will use state-of-the art cellular and molecular biological approaches coupled with non-invasive MRI (Magnetic Resonance Imaging).  The information gained from this project should provide leads to new therapeutic strategies. This research is significant in that it will provide the foundation and justification for a larger clinical trial to investigate the role of p53 in breast cancer response to long-term Tamoxifen treatment.  Such a trial, if successful, could lead to a more efficient method (as compared to the current practice of solely depending on ER-positivity) to screen patients for Tamoxifen therapy, thus moving toward personalized breast cancer therapy.

In addition to Dr. Gokul Das, PhD (Principal Investigator), other collaborating investigators are Stephen Edge, MD, formerly of Roswell Park; Carl Morrison, MD, DVM; Mukund Seshadri, PhD, DDS; Jeff Miecznikowski, PhD.