Rational Design of Human Prolactin Receptor Antagonists for Breast Cancer Therapy

摘要

There were two specific tasks listed in the proposal i.e. development of hPRL-Gl29R as a PRL receptor antagonist and development of PRL BP as PRL sequester as potential breast cancer therapeutics. The conclusion from this project are that we have demonstrated that hPRL-Gl29R has promise to be used as a breast cancer therapeutic, but no hPRL-BP. We have found that hPRL-Gl29R is able to inhibit breast cancer cell proliferation via the induction of apoptosis. We further presented evidence that shows that mechanism of hPRL- G129R induced breast cancer cell apoptosis is the regulation of Bcl-2/Bax gene expression. Data obtained from mouse breast cancer model also support the notion that is inhibition of PRL activity in breast cancer inhibit it growth. In addition, we explored the possibility of using hPRL-Gl29R as a targeting molecule by fusing it with proven effective anti-cancer agents such as immuno-modulators (IL-2) and angiogenesis inhibitors (endostatin). During past three years, we have published 10 manuscripts directly related to this subject. In summary, we have demonstrated that hPRL-Gl29R is a true PRL receptor antagonist. Its anti-breast tumor effects were confirmed using both in vitro and in vivo assays.