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Androgens Induce Invasiveness of Triple Negative Breast Cancer Cells Through AR/Src/PI3-K Complex Assembly
- Source :
- Scientific Reports, Vol 9, Iss 1, Pp 1-14 (2019), Scientific Reports
- Publication Year :
- 2019
- Publisher :
- Nature Publishing Group, 2019.
-
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.
- Subjects :
- 0301 basic medicine
Bicalutamide
medicine.drug_class
Motility
lcsh:Medicine
Triple Negative Breast Neoplasms
Article
Tosyl Compounds
Phosphatidylinositol 3-Kinases
03 medical and health sciences
0302 clinical medicine
Cell Movement
Cell Line, Tumor
Nitriles
medicine
Humans
Anilides
Neoplasm Invasiveness
Receptor
skin and connective tissue diseases
lcsh:Science
Breast cancer, androgens, androgen receptor, Src tyrosine kinase, PI3K, invasiveness
Triple-negative breast cancer
Multidisciplinary
Chemistry
lcsh:R
Androgen
Androgen receptor
src-Family Kinases
030104 developmental biology
Receptors, Androgen
Cell culture
Focal Adhesion Kinase 1
Gene Knockdown Techniques
Multiprotein Complexes
Androgens
MCF-7 Cells
Cancer research
Female
lcsh:Q
030217 neurology & neurosurgery
medicine.drug
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Volume :
- 9
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....256d2fb000d329434b6006bcef63c340