Prolactin suppresses a progestin-induced CK5-positive cell population in luminal breast cancer through inhibition of progestin-driven BCL6 expression
| Autor: | Jeffrey A. Hooke, Lynn M. Neilson, Thai H. Tran, Inna Chervoneva, Albert J. Kovatich, Hallgeir Rui, Craig D. Shriver, Chengbao Liu, Boris Freydin, Serge Y. Fuchs, Amy R. Peck, Melanie A. Girondo, Takahiro Sato, Terry Hyslop, Chelain R. Goodman |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Cellular differentiation Gene Expression Promegestone chemistry.chemical_compound Mice 0302 clinical medicine hemic and lymphatic diseases STAT5 Transcription Factor skin and connective tissue diseases 0303 health sciences education.field_of_study Progesterone Congeners 3. Good health DNA-Binding Proteins Gene Expression Regulation Neoplastic Docetaxel Receptors Estrogen 030220 oncology & carcinogenesis Proto-Oncogene Proteins c-bcl-6 Female hormones hormone substitutes and hormone antagonists medicine.drug CK5 medicine.medical_specialty prolactin Neoplasms Hormone-Dependent BCL6 Population Mice Nude Breast Neoplasms Biology progesterone Article 03 medical and health sciences Breast cancer breast cancer Internal medicine Cell Line Tumor Genetics medicine Animals Humans education Molecular Biology 030304 developmental biology Oncogene medicine.disease Stat5 Prolactin Keratin 5 Endocrinology chemistry Premenopause Cancer research Keratin-5 Neoplasm Transplantation |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | 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 anti-estrogen 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 R5020 in luminal breast cancer cells both in vitro and in vivo. CK5-positive cells were chemoresistant as determined by four-fold reduced rate of apoptosis following docetaxel exposure. Progestin-induction of CK5 was preceded by marked up-regulation 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 progestin. Prolactin suppressed progestin-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 progestin-induction of CK5-positive cells represents a novel pro-differentiation effect of prolactin in breast cancer. The present progress may have direct implications for breast cancer progression and therapy since loss of prolactin receptor-Stat5 signaling occurs frequently and BCL6 inhibitors currently being evaluated for lymphomas may have value for breast cancer. |
| Databáze: | OpenAIRE |
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