Overexpression of mitogen-activated protein kinase superfamily proteins unrelated to Ras and AF-1 of estrogen receptor alpha mutation in advanced stage human breast cancer

Transactivation of the activation function-1 (AF-1) region of the estrogen receptor alpha (ER-alpha) gene is regulated by pathway "cross-talk" from Ra s mitogen-activated protein kinase (MAPK). An analysis of this system is im portant for solving the problem of resistance to anti-estrogen agents used in the treatment of human breast cancer. We investigated the ER-alpha and R as gene mutations and the MAPK-related protein status in 103 cases of breas t cat-cinema. None of the cases showed mutations in the AF-1 region of the ER-alpha gene. Despite the extremely low frequency of K- and H-Ras mutation s in codon 12(2/103 and 0/103), Ras p21 overexpression was identified in 29 .1% (30/103), suggesting that the Ras activation in almost all cases we stu died was not caused by point mutations but by enhanced expression. Our immu nohistochemical analysis showed that the cases with overexpression of Ras a nd MAPK proteins (Ras p21, ERK-1, JNK-1, and p38) had a progressive tendenc y towards invasive growth, advanced-stage cancer, and decreased levels of E R-alpha protein. These results suggest that enhanced MAPK activity could be one of the characteristics of advanced breast cancer and that it could be involved in the transformation into estrogen-independent growth.