Characterization of metastasis regulators in human breast cancer: implications for tumor suppressor PTEN and the Rho family of small GTPases
Abstract
Cancer metastasis is a multi-faceted process requiring the disregualtion of
numerous signaling pathways, including those associated with cell adhesion and motility.
Recent data indicates strongly that growth at a primary tumor site and growth at a
metastatic site differ by the expression and/or context-dependent function of the
metastasis regulator, and that a wide variety of signaling pathways are affected. PTEN
(phosphatase and tensin homologue deleted on chromosome ten) then becomes an
attractive candidate for a metastasis suppressor, based on its ability to negatively regulate
numerous pathways involved in cell survival, cell proliferation, and cell motility.
Conversely, the Rho family of small GTPases have become attractive candidates as
contributors to metastasis. Rho GTPases regulate numerous signaling pathways involved
in cell survival, cell proliferation and cell motility, but they function to enhance these
processes instead of inhibiting them.
Data presented here demonstrates the ability of PTEN to negatively regulate
motility in human metastatic breast cancer cells without causing the cells to undergo
apoptosis. PTEN is localized in stimulated cells away from the leading edge, which
displaces it from sites of active motility signaling and prevents it from inhibiting these
processes. Furthermore, ectopic PTEN expression is shown to downregulate
phosphoinositol (3,4,5) triphosphate (PIP3), expression. Therefore, PTEN could be
acting as a metastasis suppressor in human breast cancer.
Data presented here also demonstrate the ability of the Rac subfamily of Rho
GTPases to enhance metastatic properties and contribute to metastasis. Increased Rac
activity was shown to correlate with increased metastatic potential in a panel of
metastatic human breast cancer cell variants. When activated Rac1 or Rac3 was
expressed stably in the least metastatic variant, either isoform was found to enhance
adhesion, migration, and invasion in vitro, as well as contribute to pulmonary metastasis
in the nude mouse model of experimental metastasis. Conversely, when dominant
negative Rac1 or Rac3 was expressed in the most metastatic variant, either isoform was
found to decrease adhesion, migration, and invasion in vitro, as well as block pulmonary
metastasis in vivo. Therefore, Rac1 and/or Rac3 are found to act as metastasis regulators
by negatively regulating metastatic human breast cancer progression.
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