title: Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism.
abstract: Therapy resistance remains a major problem in estrogen receptor-α (ERα)-positive breast cancer. A subgroup of ERα-positive breast cancer is characterized by mosaic presence of a minor population of ERα-negative cancer cells expressing the basal cytokeratin-5 (CK5). These CK5-positive cells are therapy resistant and have increased tumor-initiating potential. Although a series of reports document induction of the CK5-positive cells by progestins, it is unknown if other 3-ketosteroids share this ability. We now report that glucocorticoids and mineralocorticoids effectively expand the CK5-positive cell population. CK5-positive cells induced by 3-ketosteroids lacked ERα and progesterone receptors, expressed stem cell marker, CD44, and displayed increased clonogenicity in soft agar and broad drug-resistance in vitro and in vivo. Upregulation of CK5-positive cells by 3-ketosteroids required induction of the transcriptional repressor BCL6 based on suppression of BCL6 by two independent BCL6 small hairpin RNAs or by prolactin. Prolactin also suppressed 3-ketosteroid induction of CK5+ cells in T47D xenografts in vivo. Survival analysis with recursive partitioning in node-negative ERα-positive breast cancer using quantitative CK5 and BCL6 mRNA or protein expression data identified patients at high or low risk for tumor recurrence in two independent patient cohorts. The data provide a mechanism by which common pathophysiological or pharmacologic elevations in glucocorticoids or other 3-ketosteroids may adversely affect patients with mixed ERα+/CK5+ breast cancer. The observations further suggest a cooperative diagnostic utility of CK5 and BCL6 expression levels and justify exploring efficacy of inhibitors of BCL6 and 3-ketosteroid receptors for a subset of ERα-positive breast cancers.
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Goodman
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Peck
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Girondo
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: A F
authors.initials: AF
authors.lastname: Yanac
authors.affiliation: John P. Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda, MD, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Kovatich
authors.affiliation: John P. Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda, MD, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Hooke
authors.affiliation: John P. Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda, MD, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Shriver
authors.affiliation: Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: E P
authors.initials: EP
authors.lastname: Mitchell
authors.affiliation: Department of Biostatistics & Bioinformatics, Duke Cancer Institute, Duke University, Durham, NC, USA.
authors.forename: T
authors.initials: T
authors.lastname: Hyslop
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.|Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA.|Department of Pathology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Rui
mesh_terms: D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D053555:Keratin-5 / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008901:Mineralocorticoids / Q000494:pharmacology; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009368:Neoplasm Transplantation; D011372:Progestins / Q000494:pharmacology; D011379:Prognosis; D011388:Prolactin / Q000494:pharmacology; D051560:Proto-Oncogene Proteins c-bcl-6; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014183:Transplantation, Heterologous; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C084103:BCL6 protein, human; C497483:CD44 protein, human; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D005938:Glucocorticoids; D018960:Hyaluronan Receptors; D053555:Keratin-5; D008901:Mineralocorticoids; D011372:Progestins; D051560:Proto-Oncogene Proteins c-bcl-6; D034741:RNA, Small Interfering; D011980:Receptors, Progesterone; D013629:Tamoxifen; C016601:afimoxifene; D000450:Aldosterone; D003907:Dexamethasone; D004317:Doxorubicin; D011388:Prolactin