Originally published as JCO Early Release 10.1200/JCO.2005.04.3489 on July 17 2006

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Trastuzumab in Combination With Heregulin-Activated Her-2 (erbB-2) Triggers a Receptor-Enhanced Chemosensitivity Effect in the Absence of Her-2 Overexpression

Javier A. Menendez, Inderjit Mehmi, Ruth Lupu

From the Department of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston; Department of Medicine, Northwestern University Feinberg School of Medicine; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL

Address reprint requests to Ruth Lupu, PhD, Evanston Northwestern Healthcare Research Institute, 1001 University Place, Evanston, IL 60201; e-mail: r-lupu{at}northwestern.edu

Purpose: The decision for treating breast cancer patients with trastuzumab is based on HER-2 amplification and/or overexpression.

Methods: Using MCF-7 cells (Her-2 ±) engineered to overexpress heregulin (MCF-7/HRG), a ligand for the Her-2/3/4 network, we investigated whether HRG-induced transactivation of Her-2 affected breast cancer cell sensitivity to chemotherapy and whether trastuzumab trigger receptor-enhanced chemosensitivity (REC) when combined with chemotherapy without Her-2 overexpression.

Results: MCF-7/HRG cells were more than 10-fold resistant to the alkylating agent cisplatin (CDDP), while trastuzumab coexposure completely reversed HRG-promoted CDDP resistance. A synergistic interaction between trastuzumab in combination with CDDP (paclitaxel or vincristine) was obtained in MCF-7/HRG cells. Trastuzumab prevented activation of the antiapoptotic and proliferative cascades and inhibited HRG-induced Her-2/3 phosphorylation. CDDP efficacy was enhanced by trastuzumab in cells expressing endogenously high levels of HRG. Conversely, trastuzumab coexposure was ineffective in enhancing chemotherapy efficacy in cells that did not secrete HRG, such as MCF-7 cells overexpressing a structural mutated HRG isoform. Therefore, trastuzumab-induced REC, in the absence of Her-2 overexpression, occurs through the kinase activity of Her-2/3. Interestingly, HRG expression in tumor biopsies from invasive breast carcinomas (n = 189) revealed that, whereas the minority (12%) of Her-2 positive tumors (n = 60; 32%) demonstrated Her-2 phosphorylation, the majority (67%) of HRG-overexpressing and Her-2 tumors (n = 57; 30%) were in active Her-2 status.

Conclusion: We demonstrate that assessment of HRG expression and Her-2 activation define a particular breast cancer patient population for which trastuzumab plus CDDP or taxol are extremely efficient without Her-2 overexpression.

published online ahead of print at www.jco.org on July 17, 2006.

Supported by the Special Program for Research Excellence (P50CA89019-03) to R.L. Herceptin was provided by the Evanston Northwestern Healthcare Pharmacy (Evanston, IL).

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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