title: RB1 status in triple negative breast cancer cells dictates response to radiation treatment and selective therapeutic drugs.
abstract: Triple negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which only chemotherapy and radiation therapy are currently available. The retinoblastoma (RB1) tumor suppressor is frequently lost in human TNBC. Knockdown of RB1 in luminal BC cells was shown to affect response to endocrine, radiation and several antineoplastic drugs. However, the effect of RB1 status on radiation and chemo-sensitivity in TNBC cells and whether RB1 status affects response to divergent or specific treatment are unknown. Using multiple basal-like and claudin-low cell lines, we hereby demonstrate that RB-negative TNBC cell lines are highly sensitive to gamma-irradiation, and moderately more sensitive to doxorubicin and methotrexate compared to RB-positive TNBC cell lines. In contrast, RB1 status did not affect sensitivity of TNBC cells to multiple other drugs including cisplatin (CDDP), 5-fluorouracil, idarubicin, epirubicin, PRIMA-1(met), fludarabine and PD-0332991, some of which are used to treat TNBC patients. Moreover, a non-biased screen of ∼3400 compounds, including FDA-approved drugs, revealed similar sensitivity of RB-proficient and -deficient TNBC cells. Finally, ESA(+)/CD24(-/low)/CD44(+) cancer stem cells from RB-negative TNBC lines were consistently more sensitive to gamma-irradiation than RB-positive lines, whereas the effect of chemotherapy on the cancer stem cell fraction varied irrespective of RB1 expression. Our results suggest that patients carrying RB-deficient TNBCs would benefit from gamma-irradiation as well as doxorubicin and methotrexate therapy, but not necessarily from many other anti-neoplastic drugs.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tyler J W
authors.initials: TJ
authors.lastname: Robinson
authors.forename: Jeff C
authors.initials: JC
authors.lastname: Liu
authors.forename: Frederick
authors.initials: F
authors.lastname: Vizeacoumar
authors.forename: Thomas
authors.initials: T
authors.lastname: Sun
authors.forename: Neil
authors.initials: N
authors.lastname: Maclean
authors.forename: Sean E
authors.initials: SE
authors.lastname: Egan
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.forename: Alessandro
authors.initials: A
authors.lastname: Datti
authors.forename: Eldad
authors.initials: E
authors.lastname: Zacksenhaus
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D005720:Gamma Rays / Q000627:therapeutic use; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology / Q000627:therapeutic use; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000528:radiation effects; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000378:metabolism*; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*
chemical_list: D000970:Antineoplastic Agents; D016160:Retinoblastoma Protein; D004317:Doxorubicin; D008727:Methotrexate