Abstract
BackgroundMetastasis is the leading cause of death among breast cancer patients. Identifying key cellular factors controlling invasion and metastasis of breast cancer cells should pave the way to new therapeutic strategies efficiently interfering with the metastatic process. PAX2 (paired box 2) transcription factor is expressed by breast cancer cells in vivo and recently, it was shown to negatively regulate the expression of ERBB2 (erythroblastic leukemia viral oncogene homolog 2, HER-2/neu), a well-documented pro-invasive and pro-metastastic gene, in luminal/ERalpha-positive (ERα+) breast cancer cells. The objective of the present study was to investigate a putative role for PAX2 in the control of luminal breast cancer cells invasion, and to begin to characterize its regulation.ResultsPAX2 activity was higher in cell lines from luminal compared to non-luminal subtype, and activation of PAX2 by estradiol was selectively achieved in breast cancer cell lines of the luminal subtype. This process was blocked by ICI 182780 and could be antagonized by IGF-1. Knockdown of PAX2 in luminal MCF-7 cells completely abrogated estradiol-induced downregulation of ERBB2 and decrease of cell invasion, whereas overexpression of PAX2 in these cells enhanced estradiol effects on ERBB2 levels and cell invasion.ConclusionsThe study demonstrates that PAX2 activation by estradiol is selectively achieved in breast cancer cells of the luminal subtype, via ERα, and identifies IGF-1 as a negative regulator of PAX2 activity in these cells. Further, it reveals a new role for PAX2 in the maintenance of a low invasive behavior in luminal breast cancer cells upon exposure to estradiol, and shows that overexpression and activation of PAX2 in these cells is sufficient to reduce their invasive ability.
Highlights
Metastasis is the leading cause of death among breast cancer patients
Considering that luminal tumours are associated with longest disease-free survival [2], and that increased nuclear localization of PAX2 in tumour cells negatively correlates with tumour recurrence [15], preferential activation of PAX2 in poorly metastatic luminal breast cancer cells suggests that PAX2 activity confers protection against metastasis in these tumours
The highest levels of phosphorylated PAX2 protein were detected in the least invasive cell lines, and negatively correlated with protein levels of ERBB2 (Figure 1b), a major player in breast cancer cell invasion and metastasis [5,6,19]: these results support the hypothesis that PAX2 activation in luminal breast cancer cells maintains a mild invasive and metastatic behavior
Summary
Metastasis is the leading cause of death among breast cancer patients. Identifying key cellular factors controlling invasion and metastasis of breast cancer cells should pave the way to new therapeutic strategies efficiently interfering with the metastatic process. Considering that luminal tumours are associated with longest disease-free survival [2], and that increased nuclear localization of PAX2 in tumour cells negatively correlates with tumour recurrence [15], preferential activation of PAX2 in poorly metastatic luminal breast cancer cells suggests that PAX2 activity confers protection against metastasis in these tumours. Supporting this hypothesis, a recent study has revealed that PAX2 negatively regulates the expression of a well-established proinvasion and pro-metastastic gene, ERBB2 [5,6], in estradiol-treated luminal breast cancer cell lines [17]. A putative role for PAX2 as a negative regulator of invasion and metastasis in breast cancer cells, has not been pursued to this day
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