title: Prolactin suppresses a progestin-induced CK5-positive cell population in luminal breast cancer through inhibition of progestin-driven BCL6 expression.
abstract: Prolactin controls the development and function of milk-producing breast epithelia but also supports growth and differentiation of breast cancer, especially luminal subtypes. A principal signaling mediator of prolactin, Stat5, promotes cellular differentiation of breast cancer cells in vitro, and loss of active Stat5 in tumors is associated with antiestrogen therapy failure in patients. In luminal breast cancer, progesterone induces a cytokeratin-5 (CK5)-positive basal cell-like population. This population possesses characteristics of tumor stem cells including quiescence, therapy resistance and tumor-initiating capacity. Here we report that prolactin counteracts induction of the CK5-positive population by the synthetic progestin (Pg) R5020 in luminal breast cancer cells both in vitro and in vivo. CK5-positive cells were chemoresistant as determined by fourfold reduced rate of apoptosis following docetaxel exposure. Pg-induction of CK5 was preceded by marked upregulation of BCL6, an oncogene and transcriptional repressor critical for the maintenance of leukemia-initiating cells. Knockdown of BCL6 prevented induction of CK5-positive cell population by Pg. Prolactin suppressed Pg-induced BCL6 through Jak2-Stat5 but not Erk- or Akt-dependent pathways. In premenopausal but not postmenopausal patients with hormone receptor-positive breast cancer, tumor protein levels of CK5 correlated positively with BCL6, and high BCL6 or CK5 protein levels were associated with unfavorable clinical outcome. Suppression of Pg-induction of CK5-positive cells represents a novel prodifferentiation effect of prolactin in breast cancer. The present progress may have direct implications for breast cancer progression and therapy as loss of prolactin receptor-Stat5 signaling occurs frequently and BCL6 inhibitors currently being evaluated for lymphomas may have value for breast cancer.
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: T H
authors.initials: TH
authors.lastname: Tran
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Peck
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Girondo
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Goodman
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Neilson
authors.affiliation: Division of Biostatistics, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Freydin
authors.affiliation: Division of Biostatistics, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Chervoneva
authors.affiliation: Division of Biostatistics, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Hyslop
authors.affiliation: MDR Global Systems, LLC, Windber, PA, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Kovatich
authors.affiliation: Walter Reed National Military Medical Center, Bethesda, MD, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Hooke
authors.affiliation: Walter Reed National Military Medical Center, Bethesda, MD, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Shriver
authors.affiliation: Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: S Y
authors.initials: SY
authors.lastname: Fuchs
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Rui
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053555:Keratin-5 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D017697:Premenopause; D011374:Progesterone / Q000502:physiology; D045167:Progesterone Congeners / Q000494:pharmacology; D011388:Prolactin / Q000502:physiology*; D011397:Promegestone / Q000494:pharmacology; D051560:Proto-Oncogene Proteins c-bcl-6; D011960:Receptors, Estrogen / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D053555:Keratin-5; D045167:Progesterone Congeners; D051560:Proto-Oncogene Proteins c-bcl-6; D011960:Receptors, Estrogen; D050799:STAT5 Transcription Factor; D011374:Progesterone; D011388:Prolactin; D011397:Promegestone