Overexpression of IRS-4 in HER2-amplified breast cancer cells resistant to lapatinib-containing regimens
Hahn Barahona, María Belén
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Breast cancer is a heterogeneous disease in which tumors start in the cells of the breast. It's the leading cancer type for the estimated new cancer cases and second cancer type for the estimated deaths in females in the United S tates. In order to defme the prognosis of patients and to predict response to different systemic treatments, breast cancer can be grouped into major subtypes by expression of several proteins such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status. ER is expressed in 75% of all breast cancers, while HER2 is overexpressed/amplified in 20-25% of the cases; the remaining tumors are defined triple negative, since neither, ER, PR nor HER2 are overexpressed. HER2 is a member ofthe four-tyrosine kinase receptors family, which includes EGFR, HER3 and HER4. It can horno and hetero-dimerize with itself or other family members and actívate the MAPK or PI3K/ Akt pathways, which regulate cell proliferation and survival. The HER2 pathway can be pharmacologically inhibited by potent drugs, including trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of HER2, and lapatinib, a dual HERl and HER2 tyrosine kinase inhibitor. Although both of these drugs effectively block HER2 signaling, de novo and acquired resistance are common, representing a major clinical problem. lt's hypothesized that when HER2 is effectively blocked various escape pathways can be activated and induce tumor cell growth and survival, overcoming HER2 blockade. Recently, our group has identified insulin receptor substrate-4 (IRS4) as the top gene overexpressed in the lapatinibresistant and lapatinib+trastuzumab-resistant derivatives of one of our HER2-positive cell line BT474. We hypothesized that IRS4 is involved in acquired resistance to lapatinib-containing regimens, providing an escape pathway to HER2 inhibition. Our goal was to investigate whether, and by which mechanism, IRS4 is involved in resistance to HER2 targeted therapy. In order to achieve this aim, several techniques such as westem blot, polymerase chain reaction (PCR), cloning, gene overexpression and knockdown approaches were performed. W e showed for the first time a role for IRS4 in resistance to potent HER2-targeted therapy in the BT474 model. We found that upon IRS4 overexpression, HER2-positive breast cancer cells became resistant to lapatinib-containing regimens. Moreover, knockdown of IRS4, could overcome resistance to anti-HER2 therapy through the PI3K/AKT pathway in BT474 cells.