RhoC Implicated as Key Link Between Breast Cancer Stem Cells and Metastasis

Cancer researchers have identified a protein that seems to link breast cancer stem cells with the metabolic processes that lead to metastasis.

Investigators at the University of Michigan (Ann Arbor, USA) based their study on previous evidence that indicated that levels of the protein RhoC (Ras homolog gene family, member C) increase as breast cancer progresses and that a high level of RhoC is associated with poor prognosis for patient survival.

RhoC is a member of the Rho family of small GTPases, which cycle between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades. Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape, attachment, and motility. RhoC localizes to the cytoplasm and plasma membrane where it is thought to play an important role in cell locomotion. Elevated levels of this protein are associated with tumor cell proliferation and metastasis.

The investigators worked with cultures of breast cancer cells, breast cancer stem cells (BCSCs), and cells from normal breast tissue as well as with a mouse model of spontaneous metastasis.

They reported in the July 23, 2012, online edition of the journal PLoS ONE that RhoC functioned in BCSC metastasis. Inhibiting RhoC in the highly metastatic, IBC-derived SUM149 cell line revealed that RhoC was necessary for SUM149 BCSC metastasis. Conversely, overexpression of RhoC alone was sufficient to enable BCSC metastasis from the nontumorigenic, nonmetastatic MCF-10A cell line. Surprisingly, RhoC often promoted spontaneous metastasis independent from primary tumor formation even within the non-BCSC population, suggesting that RhoC could act independent of BCSC status. RhoC also influenced BCSC population size in the cell lines studied, as the abundance of BCSCs varied concurrent with changes in RhoC expression. Clinically, expression of RhoC and the BCSC marker ALDH1 strongly correlated in patient breast-cancer specimens.

“Targeting the specific molecular cogs driving the cancer stem cell machinery responsible for the cancer spreading has potential for future treatments. Eliminating cancer stem cells may ultimately be necessary to cure certain cancers, but in the meantime, we may be able to manage the cancer stem cell population and the invasive behaviors of these cells by disrupting the molecular machinery, using RhoC as a target,” said senior author Dr. Sofia D. Merajver, professor of internal medicine and epidemiology at the University of Michigan.

The investigators have designed a small molecule RhoC inhibitor that has shown good in vitro and in vivo efficacy with no apparent toxicity. However, several years of additional laboratory testing will be required before potential advancement to clinical trials in humans.

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