title: Progesterone-inducible cytokeratin 5-positive cells in luminal breast cancer exhibit progenitor properties.
abstract: Progestins play a deleterious role in the onset of breast cancer, yet their influence on existing breast cancer and tumor progression is not well understood. In luminal estrogen receptor (ER)- and progesterone receptor (PR)-positive breast cancer, progestins induce a fraction of cells to express cytokeratin 5 (CK5), a marker of basal epithelial and progenitor cells in the normal breast. CK5(+) cells lose expression of ER and PR and are relatively quiescent, increasing their resistance to endocrine and chemotherapy compared to intratumoral CK5(-)ER(+)PR(+) cells. Characterization of live CK5(+) cells has been hampered by a lack of means for their direct isolation. Here, we describe optical (GFP) and bioluminescent (luciferase) reporter models to quantitate and isolate CK5(+) cells in luminal breast cancer cell lines utilizing the human KRT5 gene promoter and a viral vector approach. Using this system, we confirmed that the induction of GFP(+)/CK5(+) cells is specific to progestins, is dependent on PR, can be blocked by antiprogestins, and does not occur with other steroid hormones. Progestin-induced, fluorescence-activated cell sorting-isolated CK5(+) cells had lower ER and PR mRNA, were slower cycling, and were relatively more invasive and sphere forming than their CK5(-) counterparts in vitro. Repeated progestin treatment and selection of GFP(+) cells enriched for a persistent population of CK5(+) cells, suggesting that this transition can be semi-permanent. These data support that in PR(+) breast cancers, progestins induce a subpopulation of CK5(+)ER(-)PR(-) cells with enhanced progenitor properties and have implications for treatment resistance and recurrence in luminal breast cancer.
authors.affiliation: Department of Pathology, University of Colorado Denver, Anschutz Medical Center, Aurora, CO, USA.
authors.forename: Sunshine Daddario
authors.initials: SD
authors.lastname: Axlund
authors.forename: Byong Hoon
authors.initials: BH
authors.lastname: Yoo
authors.forename: Rachel B
authors.initials: RB
authors.lastname: Rosen
authors.forename: Jerome
authors.initials: J
authors.lastname: Schaack
authors.forename: Peter
authors.initials: P
authors.lastname: Kabos
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Labarbera
authors.forename: Carol A
authors.initials: CA
authors.lastname: Sartorius
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D053555:Keratin-5 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D011374:Progesterone / Q000494:pharmacology*; D011372:Progestins / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism
chemical_list: C503940:KRT5 protein, human; D053555:Keratin-5; D011372:Progestins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011374:Progesterone