The ability to generate senescent progeny as a mechanism underlying breast cancer cell heterogeneity

buir.contributor.authorMumcuoğlu, Mine
buir.contributor.authorBağışlar, Sevgi
buir.contributor.authorYüzügüllü, Haluk
buir.contributor.authorAlotaibi, Hani
buir.contributor.authorŞentürk, Şerif
buir.contributor.authorTelkoparan, Pelin
buir.contributor.authorGür-Dedeoğlu, Bala
buir.contributor.authorCingöz, Burcu
buir.contributor.authorTazebay, Uygar H.
buir.contributor.authorYuluğ, Işık G.
buir.contributor.authorAkçalı, Kamil Can
buir.contributor.authorÖztürk, Mehmet
dc.contributor.authorMumcuoğlu, Mineen_US
dc.contributor.authorBağışlar, Sevgien_US
dc.contributor.authorYüzügüllü, Haluken_US
dc.contributor.authorAlotaibi, Hanien_US
dc.contributor.authorŞentürk, Şerifen_US
dc.contributor.authorTelkoparan, Pelinen_US
dc.contributor.authorGür-Dedeoğlu, Balaen_US
dc.contributor.authorCingöz, Burcuen_US
dc.contributor.authorBozkurt, B.en_US
dc.contributor.authorTazebay, Uygar H.en_US
dc.contributor.authorYuluğ, Işık G.en_US
dc.contributor.authorAkçalı, Kamil Canen_US
dc.contributor.authorÖztürk, Mehmeten_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.departmentGenetics and Biotechnology Research Center (BİLGEN)en_US
dc.description.abstractBackground Breast cancer is a remarkably heterogeneous disease. Luminal, basal-like, "normal-like", and ERBB2+ subgroups were identified and were shown to have different prognoses. The mechanisms underlying this heterogeneity are poorly understood. In our study, we explored the role of cellular differentiation and senescence as a potential cause of heterogeneity. Methodology/Principal Findings A panel of breast cancer cell lines, isogenic clones, and breast tumors were used. Based on their ability to generate senescent progeny under low-density clonogenic conditions, we classified breast cancer cell lines as senescent cell progenitor (SCP) and immortal cell progenitor (ICP) subtypes. All SCP cell lines expressed estrogen receptor (ER). Loss of ER expression combined with the accumulation of p21Cip1 correlated with senescence in these cell lines. p21Cip1 knockdown, estrogen-mediated ER activation or ectopic ER overexpression protected cells against senescence. In contrast, tamoxifen triggered a robust senescence response. As ER expression has been linked to luminal differentiation, we compared the differentiation status of SCP and ICP cell lines using stem/progenitor, luminal, and myoepithelial markers. The SCP cells produced CD24+ or ER+ luminal-like and ASMA+ myoepithelial-like progeny, in addition to CD44+ stem/progenitor-like cells. In contrast, ICP cell lines acted as differentiation-defective stem/progenitor cells. Some ICP cell lines generated only CD44+/CD24-/ER-/ASMA- progenitor/stem-like cells, and others also produced CD24+/ER- luminal-like, but not ASMA+ myoepithelial-like cells. Furthermore, gene expression profiles clustered SCP cell lines with luminal A and "normal-like" tumors, and ICP cell lines with luminal B and basal-like tumors. The ICP cells displayed higher tumorigenicity in immunodeficient mice. Conclusions/Significance Luminal A and "normal-like" breast cancer cell lines were able to generate luminal-like and myoepithelial-like progeny undergoing senescence arrest. In contrast, luminal B/basal-like cell lines acted as stem/progenitor cells with defective differentiation capacities. Our findings suggest that the malignancy of breast tumors is directly correlated with stem/progenitor phenotypes and poor differentiation potential.en_US
dc.publisherPublic Library of Scienceen_US
dc.source.titlePLoS ONEen_US
dc.subjectCD24 antigenen_US
dc.subjectCyclin dependent kinase inhibitor 1en_US
dc.subjectEstrogen receptoren_US
dc.subjectHermes antigenen_US
dc.titleThe ability to generate senescent progeny as a mechanism underlying breast cancer cell heterogeneityen_US
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
The ability to generate senescent progeny as a mechanism underlying breast cancer cell heterogeneity.pdf
872.27 KB
Adobe Portable Document Format
Full printable version