Targeting basal-like breast cancer via ‘cooperation response genes’
Basal-like breast cancer (BLBC) is a particularly aggressive and lethal form of breast cancer, with two-year patient survival rates around 20%. BLBC accounts for approximately 25% of all breast cancer, and is comprised of 6 distinct sub-types with divergent molecular features. A feature common to all sub-types of BLBC is refractory response to conventional chemotherapeutics, anti-hormonal therapies and molecularly-targeted anti-cancer agents. Thus, novel intervention targets are needed in BLBC, and should consider the potentially divergent behavior of the distinct forms of this disease.
Novel molecular targets can be found among ‘cooperation response genes’ (CRGs), essential mediators of malignant transformation synergistically regulated in response to the combination of loss-of-function mutant p53 and constitutively active Ras. Dependence on altered expression of CRGs appears to be a common feature of several aggressive epithelial cancers, as genetic and pharmacologic re-setting of CRG expression inhibits tumor formation of colon, pancreatic, and prostate cancer cells.
We have discovered that numerous CRGs are disregulated in human breast cancer, and that BLBC cells are sensitive to manipulation of CRGs by genetic and pharmacologic means. Moreover, the effects of CRG perturbations in BLBC cells appear to be very different from effects on non-transformed mammary cells. Thus, we hypothesize that CRGs are mediators of malignant transformation in BLBC, playing a cancer cell-specific regulatory role. If this is so, targeting CRGs would be a simple, efficient means of achieving cancer cell-specific, anti-BLBC intervention.
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