Research Paper Volume 14, Issue 3 pp 1200—1213

Figure 4. Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α₆β₁, but not to α_vβ₃, drives endocrine resistance in breast cancer cells. (A) Top: The binding of CCN1/CYR61 to its α₆β₁ receptor promotes myofibroblast senescence to impose self-limiting control on fibrogenesis during wound healing, thereby allowing tissue regeneration [11–13, 23, 48]. Bottom: CCN1 signaling via α₆β₁, but not via α_vβ₃, drives an endocrine resistance phenotype in ER+ breast cancer cells. (B) The interaction between CCN1 and α_vβ₃ is critical for angiogenic activities in endothelial cells and MAPK-related cell survival/chemosensitivity signaling in breast cancer cells. The interaction of CCN1 with α₆β₁ in fibroblasts is known to induce apoptosis or cellular senescence and has been widely regarded as a tumorigenesis-suppressing signaling mechanism. Here, we unveil the unforeseen capacity of CCN1 to signal through α₆β₁ in breast cancer cells to drive an endocrine resistant phenotype that might involve direct binding of CCN1 to ERα to regulate transcriptional events underlying estrogen-independence and anti-estrogen resistance in ERα-positive breast cancer cells. (ERE: Estrogen Response Elements).