In the U.S., more than 40,000 women die annually of complications of stage IV breast cancer when metastatic cancer cells compromise vital organs. Patients with breast cancers of specific subtypes are at higher risk for metastatic recurrence due to the intrinsic aggressive biology of their tumors, as well as lack of effective therapies. Moreover, the heterogeneous response of breast cancers to targeted therapies highlights the need for improved biomarkers to be used in conjunction with new therapeutic strategies. Tumors cells overcome or resist barriers to dissemination, and metastases result from coordinated biological processes that enable tumor cells to detach from the primary site (breast), invade into and travel in blood or lymphatic vessels, and grow in distant organ sites. Metastatic tumor cells survive in circulation, as well as in organ microenvironments distinct from that of the breast. In contrast, normal breast epithelial cells are not able to survive in altered or foreign matrix environments; they undergo cell death (anoikis) when deprived of signals from normal breast extracellular matrix that help maintain tissue architecture. Acquisition of invasive behavior and anoikis resistance are prerequisites for metastasis formation. The Irie Laboratory focuses on understanding how oncogenes like Akt regulate these processes and to identify novel regulators of anoikis resistance that may be developed as novel therapeutic targets for breast cancer.
1) The role of Akt isoforms in breast cancer invasion. We had previously identified opposing roles for Akt1 and Akt2 isoforms in breast cancer cell migration and invasion; Akt1 inhibits migration and induction of epithelial-to-mesenchymal transition (EMT) while Akt2 is required (Irie et al., J Cell Biology, 2005). These opposing roles reflect differential regulation of Erk/MAPK signaling. The specific mechanisms and substrates of Akt isoforms that are responsible for this dichotomous regulation are being elucidated, which has implications for Akt isoform-specific inhibitors that are in clinical development for multiple cancers.
2) Identification and evaluation of novel regulators of anoikis resistance as therapeutic targets for breast cancer. Using a high throughput siRNA “loss of function” approach, we identified novel regulators of oncogene-stimulated anoikis resistance. One candidate, PTK6, is expressed in higher risk breast cancer subtypes (Her2 and Luminal B/ER+), as well as in ovarian cancers, and is associated with poor prognosis (Irie et al., PLoS One, 2010). Inhibition of PTK6 compromises the survival of breast and ovarian cancer cells. The mechanisms responsible for regulation of survival by PTK6 and other novel candidates are being investigated. The consequences of their inhibition on breast tumor metastasis formation are being examined using in vivo models. Small molecule inhibitors of PTK6 are also being screened. The expression of PTK6 and other candidates in patient breast tumors is being examined with the expectation of developing effective biomarkers for future studies of clinical inhibitors.
Hanna Y. Irie, MD, PhD
Icahn School of Medicine
1468 Madison Avenue New York, NY 10029