title: Cytokeratin 5 positive cells represent a steroid receptor negative and therapy resistant subpopulation in luminal breast cancers.
abstract: A majority of breast cancers are estrogen receptor (ER) positive and have a luminal epithelial phenotype. However, these ER⁺ tumors often contain heterogeneous subpopulations of ER⁻ tumor cells. We previously identified a population of cytokeratin 5 (CK5) positive cells within ER⁺ and progesterone receptor positive (PR⁺) tumors that is both ER⁻PR⁻ and CD44⁺, a marker of breast tumor-initiating cells (TICs). These CK5⁺ cells have properties of TICs in luminal tumor xenografts, and we speculated that they are more resistant to chemo- and anti-ER-targeted therapies than their ER⁺ neighbors. To test this, we used ER⁺PR⁺ T47D and MCF7 breast cancer cells. CK5⁺ cells had lower proliferative indices than CK5⁻ cells, were less sensitive to 5-fluorouracil and docetaxel, and cultures became enriched for CK5⁺ cells after treatments. CK5⁺ cells were less prone to drug-induced apoptosis than CK5⁻ cells. In cells treated with 17β-estradiol (E) plus anti-estrogens tamoxifen or fulvestrant, ER protein levels decreased, and CK5 protein levels increased, compared to controls treated with E alone. In ER⁺ tumors from patients treated with neoadjuvant endocrine therapies ER gene expression decreased, and CK5 gene expression increased in post compared to pre-treatment tumors. The number of CK5⁺ cells in tumors also increased in post- compared to pre-treatment tumors. We conclude that an ER⁻PR⁻CK5⁺ subpopulation found in many luminal tumors is resistant to standard endocrine and chemotherapies, relative to the majority ER⁺PR⁺CK5⁻ cells. Compounds that effectively target these cells are needed to improve outcome in luminal breast cancers.
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Kabos
authors.forename: James M
authors.initials: JM
authors.lastname: Haughian
authors.forename: Xinshuo
authors.initials: X
authors.lastname: Wang
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Dye
authors.forename: Christina
authors.initials: C
authors.lastname: Finlayson
authors.forename: Anthony
authors.initials: A
authors.lastname: Elias
authors.forename: Kathryn B
authors.initials: KB
authors.lastname: Horwitz
authors.forename: Carol A
authors.initials: CA
authors.lastname: Sartorius
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053555:Keratin-5 / Q000235:genetics / Q000378:metabolism*; D020360:Neoadjuvant Therapy; D010641:Phenotype; D011980:Receptors, Progesterone / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C503940:KRT5 protein, human; D053555:Keratin-5; D011980:Receptors, Progesterone; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol