A highly invasive subpopulation of MDA-MB-231 breast cancer cells shows accelerated growth, differential chemoresistance, features of apocrine tumors and reduced tumorigenicity in vivo
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Adriana Amaro1,*, Giovanna Angelini1,*, Valentina Mirisola1, Alessia Isabella Esposito1, Daniele Reverberi1, Serena Matis1, Massimo Maffei1, Walter Giaretti1, Maurizio Viale2, Rosaria Gangemi2, Laura Emionite3, Simonetta Astigiano4, Michele Cilli3, Beatrice E. Bachmeier5, Peter H. Killian5, Adriana Albini6, Ulrich Pfeffer1
1Molecular Pathology, IRCCS AOU San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy
2Biotherapy, IRCCS AOU San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy
3Animal Facility, IRCCS AOU San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy
4Immunology, IRCCS AOU San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy
5Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany
6Scientific and Technology Park, IRCCS MultiMedica, Milan, Italy
*These authors have contributed equally to the work
Adriana Albini, email: [email protected]
Ulrich Pfeffer, email: [email protected]
Keywords: breast cancer, invasion, apocrine breast cancer, metastasis, aneuploidy
Received: May 16, 2016 Accepted: August 13, 2016 Published: September 10, 2016
The acquisition of an invasive phenotype is a prerequisite for metastasization, yet it is not clear whether or to which extent the invasive phenotype is linked to other features characteristic of metastatic cells. We selected an invasive subpopulation from the triple negative breast cancer cell line MDA-MB-231, performing repeated cycles of preparative assays of invasion through Matrigel covered membranes. The invasive sub-population of MDA-MB-231 cells exhibits stronger migratory capacity as compared to parental cells confirming the highly invasive potential of the selected cell line. Prolonged cultivation of these cells did not abolish the invasive phenotype. ArrayCGH, DNA index quantification and karyotype analyses confirmed a common genetic origin of the parental and invasive subpopulations and revealed discrete structural differences of the invasive subpopulation including increased ploidy and the absence of a characteristic amplification of chromosome 5p14.1-15.33. Gene expression analyses showed a drastically altered expression profile including features of apocrine breast cancers and of invasion related matrix-metalloproteases and cytokines. The invasive cells showed accelerated proliferation, increased apoptosis, and an altered pattern of chemo-sensitivity with lower IC50 values for drugs affecting the mitotic apparatus. However, the invasive cell population is significantly less tumorigenic in orthotopic mouse xenografts suggesting that the acquisition of the invasive capacity and the achievement of metastatic growth potential are distinct events.
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