Cancer Selective Targeting Through a Cancer Specific Gene Network
Basal-like breast cancer (BLBC) is an aggressive, hard-to-treat cancer, with frequent metastasis, recurrence, and poor long-term survival. BLBCs are resistant to cancer-selective agents used to treat breast cancers (e.g., Tamoxifen and Herceptin). Thus, standard of care for BLBC involves highly cytotoxic chemotherapeutic agents that still fail in ˜80% of cases.
My laboratory has discovered a key role for 'cooperation response genes' (CRGs), non-mutant regulators of cancer growth, which control tumor formation in BLBC. CRGs are organized in a 'gene regulatory network', with CRGs interacting to control expression of other CRGs in the cancer cell. These 'ripple effects' mean that changing the expression of one CRG can lead to changes in expression of additional CRGs, providing an explanation as to how numerous individual CRG perturbations can inhibit tumor formation. Moreover, genetic or pharmacologic targeting of CRGs is cancer selective, inhibiting cancer growth while sparing normal cell function.
Our long term goal is to identify and understand the molecular construction of cancer cell-specific gene networks, to exploit these for selective anti-cancer targeting. We propose that interactions within the CRG network are unique to and essential for cancer cells, explaining why targeting this network produces cancer cell-specific inhibition. Studies are ongoing to examine the relationships between CRGs in non-cancerous breast cells, contrasting these to the CRG network observed in BLBC cells, and to test whether BLBC-specific growth arrest in response to changes in CRG expression depends on cancer-specific interactions within the CRG network. Moreover, we are examining the impact on the CRG network of drugs with selective anti-BLBC activity. This project will provide key information to inform our understanding of the CRG network, revealing molecular mechanisms underlying cancer-specific effects of targeting CRGs, and how those relate to candidate anti-BLBC drugs aimed at the CRGs.