CDR formation requires activation of both the protein regulator of actin polymerization N-WASP, mediated by ERK1/2, and of the actin-depolymerizing protein cofilin, mediated by EGFR/ERBB1. Furthermore, this latter event may be inhibited by the negative cell motility regulator p140Cap, as we found that p140Cap overexpression led to cofilin deactivation and inhibition of CDR formation. Normal cell division—mitosis—has checkpoints that keep cell division under control. Some of the proteins that control this cycle are called cdk2 (CDKs). Overexpression of HER2 sidesteps these checkpoints, causing cells to proliferate in an uncontrolled fashion. This is caused by phosphorylation by Akt.Trastuzumab binds to domain IV of the extracellular segment of the HER2/neu receptor. Monoclonal antibodies that bind to this region have been shown to reverse the phenotype of HER2/neu expressing tumor cells. Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferation. It has been suggested that trastuzumab does not alter HER-2 expression, but downregulates activation of AKT. In addition, trastuzumab suppresses angiogenesis both by induction of antiangiogenic factors and repression of proangiogenic factors. It is thought that a contribution to the unregulated growth observed in cancer could be due to proteolytic cleavage of HER2/neu that results in the release of the extracellular domain. One of the most relevant proteins that trastuzumab activates is the tumor suppressor p27 (kip1), also known as CDKN1B.
History
The drug was first discovered by scientists including Dr. Axel Ullrich and Dr. H. Michael Shepard at Genentech, Inc. in South San Francisco, CA. Earlier discovery about the neu oncogene by Robert Weinbergs lab  and the monoclonal antibody recognizing the oncogenic receptor by Mark Greenes lab  also contributed to the establishment of HER2 targeted therapies. Dr. Dennis Slamon subsequently worked on trastuzumabs development. A book about Dr. Slamons work was made into a television film called Living Proof, that premiered in 2008. Genentech developed trastuzumab jointly with UCLA, beginning the first clinical trial with 15 women in 1992. By 1996, clinical trials had expanded to over 900 women, but due to pressure from advocates based on early success, Genentech worked with the FDA to begin a lottery system allowing 100 women each quarter access to the medication outside the trials. Herceptin was Fast-tracked by the FDA and gained approval in September 1998.Biocon Ltd and its partner Mylan obtained regulatory approval to sell a biosimilar in 2014, but Roche contested the legality of the approval; that litigation ended in 2016, and Biocon and Mylan each introduced their own branded biosimilars. Society and culture
Economics
Trastuzumab costs about US$70,000 for a full course of treatment, Trastuzumab brought in $327 million in revenue for Genentech in the fourth quarter of 2007.Australia has negotiated a lower price of A$50,000 per course of treatment.Since October 2006, trastuzumab has been made available for Australian women and men with early-stage breast cancer via the Pharmaceutical Benefits Scheme.