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β₁-Integrin Circumvents the Antiproliferative Effects of Trastuzumab in Human Epidermal Growth Factor Receptor-2–Positive Breast Cancer

Departments of ¹ Experimental Oncology, ² Laboratory Medicine and Pathology, ³ Radiation Oncology, ⁴ Statistics and Epidemiology, and ⁵ Medical Oncology, Cross Cancer Institute and University of Alberta, Edmonton, Alberta, Canada

Requests for reprints: Bassam Abdulkarim, Department of Oncology, Cross Cancer Institute and University of Alberta, 11560 University Avenue, Edmonton, Alberta, Canada T6G 1Z2. Phone: 780-432-8517; Fax: 780-432-8380; E-mail: bassamab{at}cancerboard.ab.ca.

Resistance to trastuzumab, the monoclonal antibody targeting human epidermal growth factor receptor 2 (HER-2), is a major concern for HER-2–positive metastatic breast cancer (MBC) patients. To date, HER-2 status is the only available biomarker for selecting patients for trastuzumab-based therapy. β₁-Integrin, an adhesion molecule involved in cell survival and drug resistance, shares common downstream signaling elements with HER-2, such as the phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase-1/2 (ERK1/2) pathways. The significance of β₁-integrin expression in HER-2–positive breast cancer and its involvement in a patient's response to trastuzumab-based therapy are unknown. We show here that overexpression of β₁-integrin is an independent negative prognostic factor for tumor progression of HER-2–positive MBC patients treated with trastuzumab-based chemotherapy. Enforced overexpression of β₁-integrin, its small interfering RNA–induced knockdown or treatment with a β₁-integrin–blocking antibody in HER-2–positive breast cancer cells, identified a strong inverse relationship between expression level of β₁-integrin and in vitro sensitivity to trastuzumab. Notably, β₁-integrin overexpression increased the phosphorylation of Akt-Ser473 and ERK1/2, thereby promoting survival and mitogenic signals to bypass the antiproliferative effects of trastuzumab. Our findings show that β₁-integrin provides a novel independent prognostic biomarker of trastuzumab response in HER-2–positive MBC patients and suggest a new target to augment the antiproliferative effects of trastuzumab. [Cancer Res 2009;69(22):8620–8]

Key Words: β₁-integrin • HER-2 • metastatic breast cancer • trastuzumab