LMW-PTP isoforms Regulate Breast Cancer Cells Migration through a RhoA Dependent Mechanism

Although low-molecular weight protein tyrosines phosphatase (LMW-PTP) has been associated with tumorigenesis and tumor progression, its role is controversial. In this study, we show that alterations in the RhoA activation status caused by knocking-down separately the two main isoforms of LMW-PTP, fast and slow, interfere with the migratory potential of breast cancer cells. Our results highlight the differential role of LMW-PTP isoforms in cancer biology. Therefore, novel therapeutic approaches should take this into account - targeting LWM-PTP isoforms and not LMW-PTP as a whole.

Authors and affiliations:

Irina Alho1,2, Luís Costa2,3, Manuel Bicho1  and Constança Coelho1

1. Genetics Laboratory, Lisbon Medical School, Lisbon, Portugal;

2. Institute of Molecular Medicine, Lisbon, Portugal;

3. Medical Oncology Department, Oncology Division, Santa Maria Hospital, Hospital, North Lisbon Hospital Center, Lisbon, Portugal

Abstract:

Low molecular weight protein tyrosine phosphatase (LMW-PTP) has been associated with cell proliferation control through dephosphorylation and inactivation of growth factor receptors such as PDGF-R and EphA2, and with cellular adhesion and migration through p190RhoGap and RhoA. We aim to clarify the role of two main LMW-PTP isoforms in breast cancer tumorigenesis. We used a siRNA-mediated loss-of-function in MDA-MB-435 breast cancer cell line to study the role of the two main LMW-PTP isoforms, fast and slow, in breast cancer tumorigenesis and migration. Our results show that the siRNAs directed against total LMW-PTP and LMW-PTP slow isoform enhanced cell motility in an invasive breast cancer cell line, MDA-MB-435, with no changes in the proliferation and invasive potential of cells. The total LMW-PTP knockdown caused a more pronounced increase of cell migration. Suppression of total LMW-PTP decreased RhoA activation and suppression of the LMW-PTP slow isoform caused a small but significant increase in RhoA activation. We propose that the increase or decrease in RhoA activation induces changes in stress fibers formation and consequently alter the adhesive and migratory potential of cells. These findings suggest that the two main isoforms of LMW-PTP may act differentially, with the fast isoform having a more prominent role in tumor cell migration. In addition, our results highlight functional specificity among LMW-PTP isoforms, suggesting hitherto unknown roles for these proteins in breast cancer biology. Novel therapeutic approaches targeting LMW-PTP, considering the expression of these two isoforms and not LMW-PTP as a whole, should be investigated.

Journal:

PLoS One

Link:

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0076307