RhoB Differentially Controls Akt Function in Tumor Cells and Stromal Endothelial Cells during Breast Tumorigenesis

Abstract

Tumors are composed of cancer cells but also a larger number of diverse stromal cells in the tumor microenvironment. Stromal cells provide essential supports to tumor pathophysiology but the distinct characteristics of their signaling networks are not usually considered in developing drugs to target tumors. This oversight potentially confounds proof-of-concept studies and increases drug development risks. Here, we show in established murine and human models of breast cancer how differential regulation of Akt by the small GTPase RhoB in cancer cells or stromal endothelial cells determines their dormancy versus outgrowth when angiogenesis becomes critical. In cancer cells in vitro or in vivo, RhoB functions as a tumor suppressor that restricts EGF receptor (EGFR) cell surface occupancy as well as Akt signaling. However, after activation of the angiogenic switch, RhoB functions as a tumor promoter by sustaining endothelial Akt signaling, growth, and survival of stromal endothelial cells that mediate tumor neoangiogenesis. Altogether, the positive impact of RhoB on angiogenesis and progression supercedes its negative impact in cancer cells themselves. Our findings elucidate the dominant positive role of RhoB in cancer. More generally, they illustrate how differential gene function effects on signaling pathways in the tumor stromal component can complicate the challenge of developing therapeutics to target cancer pathophysiology.

Minireview: Mouse Models of Rho GTPase Function in Mammary Gland Development, Tumorigenesis, and Metastasis

“…Consistent with this, RhoB deletion enhanced the frequency and reduced the latency of tumor formation in MMTV-PyMT mice (13). However, tumors that formed in RhoB knockout mice grew more slowly and had reduced angiogenesis.…”

“…Thus, results of such studies must be interpreted with caution. Whole body deletion of RhoB or RhoC did not elicit large changes in mammary gland development, as these animals were able to nurse their young (12)(13)(14). Mammary gland-specific deletion of Rac1 also did not affect gland development during puberty or pregnancy (15).…”

RhoB loss induces Rac1-dependent mesenchymal cell invasion in lung cells through PP2A inhibition

“…Notably, it was reported that RhoB has a critical role in angiogenesis and controls stromal endothelial cells during breast tumorigenesis. 23,39 Among the transcriptional factors involved in mesenchymal migration, we observed that Slug, one of the most thoroughly investigated EMT regulators in lung cancer, 40 was strongly induced following RhoB loss. In parallel, E-cadherin, epithelial marker of EMT known to be downregulated notably by Slug, showed reduced levels of mRNA and protein.…”

Rho GTPases and cancer

“…Recently RhoB expression was reported to be increased in endothelial cells of the tumor stroma compared to adjacent normal tissue . Knockout experiments support a role for RhoB in tumor angiogenesis.…”