Abstract
Breast cancer (BC) is still characterized by high morbidity and mortality. A specific BC subtype named triple negative BC (TNBC) lacks estrogen and progesterone receptors (ER and PR, respectively) and is characterized by the absence of overexpression/amplification of human epidermal growth factor receptor 2 (HER2). The androgen receptor (AR) is expressed in TNBC, although its function in these cancers is still debated. Moreover, few therapeutic options are currently available for the treatment of TNBC. In this study, we have used TNBC-derived MDA-MB231 and MDA-MB453 cells that, albeit at different extent, both express AR. Androgen challenging induces migration and invasiveness of these cells. Use of the anti-androgen bicalutamide or AR knockdown experiments show that these effects depend on AR. Furthermore, the small peptide, S1, which mimics the AR proline-rich motif responsible for the interaction of AR with SH3-Src, reverses the effects in both cell lines, suggesting that the assembly of a complex made up of AR and Src drives the androgen-induced motility and invasiveness. Co-immunoprecipitation experiments in androgen-treated MDA-MB231 and MDA-MB453 cells show that the AR/Src complex recruits p85α, the regulatory subunit of PI3-K. In such a way, the basic machinery leading to migration and invasiveness is turned-on. The S1 peptide inhibits motility and invasiveness of TNBC cells and disrupts the AR/Src/p85α complex assembly in MDA-MB231 cells. This study shows that the rapid androgen activation of Src/PI3-K signaling drives migration and invasiveness of TNBC cells and suggests that the S1 peptide is a promising therapeutic option for these cancers.
Highlights
High-throughput approaches have identified several therapeutic targets in triple negative Breast cancer (BC) (TNBC), such as the effectors of PI3-K- or Ras-dependent pathways
The amount of androgen receptor (AR) expressed in MDA-MB453 was higher than that observed in MDA-MB231 (Fig. 1, panel c) cells and similar to that detected in prostate cancer-derived LNCaP cells (Fig. 1, panel b)
Evidence so far collected suggests that AR fosters BC proliferation when ER is expressed, while it is associated with a worse outcome and a higher risk of recurrences in TNBC37
Summary
High-throughput approaches have identified several therapeutic targets in TNBC, such as the effectors of PI3-K- or Ras-dependent pathways. A TNBC subtype is characterized by the expression of luminal androgen receptor (LAR) in the presence of a luminal-like expression signature MDA-MB231 and MDA-MB453 cells that represent the mesenchyme and the LAR subtype of TNBC, respectively[17,18] have been used As these cells express AR, we have investigated whether androgens activate rapid signaling pathways involved in cell invasiveness. Our results identify a previously uncharacterized role for the hormone-regulated AR/Src complex assembly and the consequent invasiveness of TNBC cells. They indicate that the AR/Src complex and its dependent pathway might represent a good network to target using the new S1 peptide in preclinical and clinical models of TNBC
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