Involvement of Ras Activation in Human Breast Cancer Cell Signaling, Invasion, and Anoikis

Abstract

Although mutated forms of ras are not associated with the majority of breast cancers (<5%), there is considerable experimental evidence that hyperactive Ras can promote breast cancer growth and development. Therefore, we determined whether Ras and Ras-responsive signaling pathways were activated persistently in nine widely studied human breast cancer cell lines. Although only two of the lines harbor mutationally activated ras, we found that five of nine breast cancer cell lines showed elevated active Ras-GTP levels that may be due, in part, to HER2 activation. Unexpectedly, activation of two key Ras effector pathways, the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT signaling pathways, was not always associated with Ras activation. Ras activation also did not correlate with invasion or the expression of proteins associated with tumor cell invasion (estrogen receptor ␣ and cyclooxygenase 2). We then examined the role of Ras signaling in mediating resistance to matrix deprivationinduced apoptosis (anoikis). Surprisingly, we found that ERK and phosphatidylinositol 3-kinase/AKT activation did not have significant roles in conferring anoikis resistance. Taken together, these observations show that Ras signaling exhibits significant cell context variations and that other effector pathways may be important for Ras-mediated oncogenesis, as well as for anoikis resistance, in breast cancer. Additionally, because ERK and AKT activation are not strictly associated with Ras activation, pharmacological inhibitors of these two signaling pathways may not be the best approach for inhibition of aberrant Ras function in breast cancer treatment.

The cell cycle regulator ecdysoneless cooperates with H-Ras to promote oncogenic transformation of human mammary epithelial cells

“…While oncogenic mutations of Ras are less frequent in breast cancer, 27 overexpression of mutant Ras in hMEC and other epithelial transformation models is well-established as a strategy to reveal cooperating oncogenic roles of other genes. [28][29][30] Notably, mutations in components of the Ras pathways, such as MAPK, AKT and ERK, are frequently altered in breast cancer, [31][32][33][34] and Ras functions downstream of receptor tyrosine kinases such as ErbB2 that are major drivers of breast cancers. 35 In this context, Ecd overexpression together with ErbB2 signifies an especially poor prognosis.…”

Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells

“…Because detached cells normally undergo apoptosis (23)(24)(25), a critical first step in cancer progression is the development of resistance to matrix deprivation-induced apoptosis (anoikis) (26,27). Therefore, to investigate the mechanism of E 2 -prolonged survival of ELT3 cells in the circulation, we examined the effect of estrogen on anoikis.…”

Id1 cooperates with oncogenic Ras to induce metastatic mammary carcinoma by subversion of the cellular senescence response

“…Breast cancers also commonly exhibit elevated Ras activity (23,24). Because we have overexpressed oncogenic Ras, it is possible that we have induced senescence by driving levels of Ras activation not seen in human cancer.…”