Abstract
Activating protein-1 (AP-1) family members, especially Fra-1 and c-Jun, are highly expressed in invasive cancers and can mediate enhanced migration and proliferation. The aim of this study was to explore the significance of elevated levels of AP-1 family members under conditions that restrict growth. We observed that invasive MDA-MB-231 cells express high levels of Fra-1, c-Jun, and Jun-D during serum starvation and throughout the cell cycle compared to non-tumorigenic and non-invasive cell lines. We then analyzed Fra-1 levels in additional breast and other cancer cell lines. We found breast and lung cancer cells with higher levels of Fra-1 during serum starvation had relatively higher ability to proliferate and migrate under these conditions. Utilizing a dominant negative construct of AP-1, we demonstrated that proliferation and migration of MDA-MB-231 in the absence of serum requires AP-1 activity. Finally, we observed that MDA-MB-231 cells secrete factors(s) that induce Fra-1 expression and migration in non-tumorigenic and non-metastatic cells and that both the expression of and response to these factors require AP-1 activity. These results suggest the presence of an autocrine/paracrine loop that maintains high Fra-1 levels in aggressive cancer cells, enhancing their proliferative and metastatic ability and affecting neighbors to alter the tumor environment.
Highlights
Activating protein-1 (AP-1) is a dimeric transcription factor typically comprised of one member each from the Fos and Jun families [1, 2]
Studies of exponentially growing breast cancer cells have demonstrated that some AP-1 family members such as Fos related antigen-1 (Fra-1) and c-Jun are highly expressed in invasive cell lines compared to less invasive ones [19, 21]
Most of the AP-1 family members’ expression is low in serum starved MCF10A and MDA-MB-468 cells and increased upon serum addition, similar to what was first described in mouse fibroblasts [9, 10]. Both c-Fos and c-Jun increase early after introduction of serum, while Fra-1 and JunD increase later, and this is associated with a reduction in the level of c-Fos, which return to basal levels at 12 hours
Summary
Activating protein-1 (AP-1) is a dimeric transcription factor typically comprised of one member each from the Fos and Jun families [1, 2]. At the same time, c-Fos and c-Jun were determined to be cellular homologs of viral oncogenes [4,5,6] Soon after that, they were recognized as components of AP-1 that together bind the AP-1 response sequence. C-Fos expression decreases [10] and Fra-1 increases, resulting in a shift from c-Fos/AP-1 to Fra-1/AP-1 [12] and presumably helping cells past the restriction point by inducing cyclin D1 [13, 14]. This change in expression occurs via DNA binding in which c-Fos induces Fra-1 via an AP-1 binding site in the Fra-1 promoter [15, 16] and in return Fra-1 turns off c-Fos by binding to the c-Fos promoter [17]
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