hMENA11acontributes to HER3-mediated resistance to PI3K inhibitors in HER2-overexpressing breast cancer cells

Human Mena (hMENA), an actin regulatory protein of the ENA/VASP family, cooperates with ErbB receptor family signaling in breast cancer. It is overexpressed in high-risk preneoplastic lesions and in primary breast tumors where it correlates with HER2 overexpression and an activated status of AKT and MAPK. The concomitant overexpression of hMENA and HER2 in breast cancer patients is indicative of a worse prognosis. hMENA is expressed along with alternatively expressed isoforms, hMENA11aand hMENAΔv6 with opposite functions. A novel role for the epithelial-associated hMENA11aisoform in sustaining HER3 activation and pro-survival pathways in HER2-overexpressing breast cancer cells has been identified by reverse phase protein array and validated in vivo in a series of breast cancer tissues. As HER3 activation is crucial in mechanisms of cell resistance to PI3K inhibitors, we explored whether hMENA11ais involved in these resistance mechanisms. The specific hMENA11adepletion switched off the HER3-related pathway activated by PI3K inhibitors and impaired the nuclear accumulation of HER3 transcription factor FOXO3a induced by PI3K inhibitors, whereas PI3K inhibitors activated hMENA11aphosphorylation and affected its localization. At the functional level, we found that hMENA11asustains cell proliferation and survival in response to PI3K inhibitor treatment, whereas hMENA11asilencing increases molecules involved in cancer cell apoptosis. As shown in three-dimensional cultures, hMENA11acontributes to resistance to PI3K inhibition because its depletion drastically reduced cell viability upon treatment with PI3K inhibitor BEZ235. Altogether, these results indicate that hMENA11ain HER2-overexpressing breast cancer cells sustains HER3/AKT axis activation and contributes to HER3-mediated resistance mechanisms to PI3K inhibitors. Thus, hMENA11aexpression can be proposed as a marker of HER3 activation and resistance to PI3K inhibition therapies, to select patients who may benefit from these combined targeted treatments. hMENA11aactivity could represent a new target for antiproliferative therapies in breast cancer.