Development of Biologically Based Therapies for Basal-like Breast Tumors

There have been many experiments on breast cancer cell lines and tumors with respect to identifying genes/pathways that are involved in cancer initiation, progression and response to therapy; however, only a few actually make suggestions that might affect treatment. The knowledge that breast cancer actually represents several diseases that arise from at least two different epithelial cells has been a major stepping-stone for stratifying patients and identifying more selective and biology-based therapies. Drugs aimed at the estrogen receptor, estrogen production, and HER2 have been very successful in the many patients whose tumors are dependent upon these signaling pathways for growth. Unfortunately for tumors that lack these markers, such as basal-like subtype, there are few treatment options. Until recently, few studies had actually considered if there were subtype-specific differences in response to chemotherapy. This dissertation focuses on the basal-like subtype of cancer and examines responses to chemotherapeutics relative to the luminal subtypes and evaluates the EGFR pathway as a place for potential therapeutic intervention. In response to two chemotherapeutics - doxorubicin and 5-fluorouracil - a general stress response was the dominant profile and this profile varied both in vitro and in vivo between the subtypes. The drug-specific response was more similar in the subtypes. A predictive gene list was identified that could predict both subtype and drug treatment with fairly high accuracy suggesting some degree of subtype-specific mechanism of action. The different responses to doxorubicin and 5-fluorouracil led us to evaluate sensitivity to a larger panel of drugs and cell lines and we determined that the basal-like subtype was more sensitive to carboplatin. While identification of chemotherapy regimens that are beneficial to the basal-like subtype is needed, drugs targeted to specific deregulated pathways in this subtype will be more effective in the long run. My work evaluated the EGFR pathway and determined it is high in 90% of all basal-like tumors, but I also identified high expression of genes downstream of EGFR that can induce EGFR-independent activation of this pathway. My data suggest that inhibition of MEK or PI3K, along with chemotherapeutics, may be an effective regimen for basal-like patients