Abstract
p73 is expressed as TA and ΔN isoforms, both of which are implicated in tumor suppression and/or promotion. To address how p73 possesses these opposing functions, we developed three-dimensional culture of MCF10A cells, which undergo cell morphogenesis to form polarized spheroids with hollow lumen similar to normal mammary acini in vivo. Here, we showed that upon knockdown of p73, particularly TAp73 but not ΔNp73, MCF10A cells formed irregular and near-normal acini without hollow lumen in three-dimensional culture. We also found that upon knockdown of p73 or TAp73, but not ΔNp73, MCF10A cells underwent epithelial-to-mesenchymal transition (EMT) via down-regulation of E-cadherin coupled with up-regulation of β-catenin and laminin V. In addition, we found that Snail-1, Slug, and Twist, all of which are known to act as EMT inducers by repressing E-cadherin expression, were increased markedly upon knockdown of p73 and TAp73 but little if any by ΔNp73. Furthermore, we showed that knockdown of p73 or TAp73 in MCF10A cells led to a marked increase in cell proliferation and migration. Together, our data suggest that TAp73 is necessary for maintaining normal cell polarity by suppressing EMT.
Highlights
Both TAp73 and ⌬Np73 are implicated in tumor suppression or promotion
We found that upon knockdown of p73 or TAp73, but not ⌬Np73, MCF10A cells underwent epithelial-to-mesenchymal transition (EMT) via down-regulation of E-cadherin coupled with up-regulation of -catenin and laminin V
We showed that knockdown of p73 or TAp73 in MCF10A cells led to a marked increase in cell proliferation and migration
Summary
Both TAp73 and ⌬Np73 are implicated in tumor suppression or promotion. the underlying mechanism remains unclear. To address how p73 possesses these opposing functions, we developed three-dimensional culture of MCF10A cells, which undergo cell morphogenesis to form polarized spheroids with hollow lumen similar to normal mammary acini in vivo. We showed that upon knockdown of p73, TAp73 but not ⌬Np73, MCF10A cells formed irregular and near-normal acini without hollow lumen in three-dimensional culture. To address how oncogenes or tumor suppress genes influence mammary epithelial cell polarity, three-dimensional culture of immortalized MCF10A cells, which form an acinar structure remarkably similar to the normal acinus in vivo, was established and used widely [21,22,23,24,25,26]. To address how p73 is involved in tumor suppression and promotion via regulation of cell polarity, we generated MCF10A cell lines in which p73 or p73 isoforms were knocked down stably. Our study provides an insight into how p73 has two opposing functions in tumor suppression and promotion
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