The role of protein tyrosine kinases such as Her2 in breast cancer growth has been well-established (Yu and Huang, 2000
), whereas the contribution of protein tyrosine phosphatases has been mostly unexplored. In this report, we showed that the tyrosine phosphatase PTPH1 is over-expressed in primary human breast cancer and its increased protein expression further correlates with the clinical metastasis. Furthermore, PTPH1 was shown to stimulate breast cancer growth independent of phosphatase activity likely through increasing cytoplasmic VDR protein expression via a complex formation thereby forming a positive feedback loop leading to their mutual stabilization. This was demonstrated by the following: 1) PTPH1 stimulates breast cancer growth and increases VDR protein expression in several breast cancer cell lines; 2) depletion of induced VDR abolishes the PTPH1 oncogenic activity and PTPH1 also loses its growth stimulatory activity in VDR−/− cells; 3) PTPH1 is exclusively cytoplasmic and only regulates cytoplasmic VDR protein expression; 4) PTPH1 binds and stabilizes VDR protein; 5) PTPH1 protein expression is also decreased in VDR depleted or knockout cells and there is a reduced PTPH1 protein stability in VDR−/− cells compared to their +/+ counterparts, indicating their mutual stabilization effect; and 6) a nuclear-localization deficient VDR loses its growth inhibitory activity. Thus, up-regulated cytoplasmic VDR may cooperate with PTPH1 to stimulate breast cancer growth through their complex formation and mutual stabilization (). These results together reveal a new role of a protein tyrosine phosphatase in regulating breast cancer growth through signaling cross-talk with a nuclear receptor.
So far only few PTPs have been reported to be involved in regulating breast cancer growth. A tumor-suppressor function, for example, has been proposed for the protein tyrosine phosphatase alpha (PTPα
) that inhibits in vitro breast cancer growth but is paradoxically over-expressed in 29% of primary breast cancer (Ardini et al., 2000
). The phosphatase PTP1B, on the other hand, is hyperexpressed in primary breast tumors (Wiener et al., 1994
) and required for Her-2 induced breast epithelial cell transformation in vitro (Arias-Romero et al., 2009
) and for Her-2 resultant mammary tumor development in mice (Bentires-Alj and Neel, 2007
). However, PTP1B inhibits the transformation in fibroblasts by Her-2 (Brown-Shimer et al., 1992
) and Ras (Liu and Chernoff, 1998
) and no studies so far have shown a role of PTP1B in regulating human breast cancer growth. PTPH1, on the other hand, is induced by Ras and overexpressed in primary colon (Hou et al., 2010
) and breast cancers (), and stimulates the malignant growth in both ER+ and ER− breast cancer (). To our knowledge, this may be the first report showing that an over-expressed PTP in primary breast tumors acutely promotes human breast cancer growth. Further experiments are needed to investigate if PTPH1 promotes breast cancer growth in vivo and whether PTPH1 signals through Ras and/or Her-2 to increase breast cancer development and progression.
Our result that a nuclear-localization deficient VDR loses its growth-inhibitory activity is consistent with the conclusion that PTPH1 may increase breast cancer growth through increasing cytoplasmic VDR expression and resultant mutual stabilization. Although previous studies implicate that only nuclear VDR is transcriptional active (Prufer et al., 2000
; Prufer et al., 2002
) and/or growth inhibitory (Garay et al., 2007
; Yang et al., 2001
), no studies reported thus far have directly demonstrated a functional role of the NLS in VDR regulating malignant growth. While VDR/mNLS expressed cells tend to be more proliferative than the vector control, its enforced expression alone failed to significantly increase breast cancer cell growth (), indicating that the cytoplasmic receptor may only act to assist other associated oncoproteins, such as PTPH1, to promote the malignant growth. In supporting this speculation, two recent clinical studies showed that increased cytoplamic VDR protein expression in primary lung cancer predicts an advanced stage of the disease (Menezes et al., 2008
) and in primary colon cancer correlates with PIK3CA and K-Ras mutations (Kure et al., 2009
). It would be of great interest to investigate further if increased PTPH1 expression in primary breast cancer couples with elevated cytoplasmic VDR expression and whether such combined up-regulations predict a poor clinic outcome. Studies of the signaling cross-talk between PTPH1 and VDR may reveal a novel strategy for cancer therapeutic targeting by regulating PTPH1 expression and/or VDR localizations.