Induction of a therapy-resistant cytokeratin 5-positive cell population by 3-ketosteroids in luminal breast cancer
Abstract
More than 30% of patients with luminal breast cancer experience local recurrence or metastatic disease subsequent to diagnosis and treatment. The reemergence of these cancers implies the presence of a dormant population of therapy–resistant, tumor–initiating cells that are able to evade treatment and repopulate a tumor years following treatment. Progestins have been shown to induce the emergence of a population of CK5+ cells that have decreased sensitivity to therapy and increased tumorigenic potential. Whether other 3–ketosteroids are able to induce a CK5+ cell population in luminal breast cancers is unknown, but would be clinically informative for patient management. In this thesis, we address four questions: 1) Is the induction of CK5+ cells by Prg more generalizable to 3–ketosteroids and, if so, do CK5+ cells induced by other 3–ketosteroids also exhibit tumor-initiating and therapy-resistant properties? 2) What is the mechanism mediating 3–ketosteroid induction of CK5+ cells? 3)) Is prolactin, through inhibition of this mediator, able to suppress the 3–ketosteroid induction of CK5+ cells and their ability to survive chemo– and antiestrogen therapies? and 4) Does presence of CK5+ cells in 3–ketosteroid receptor–positive luminal breast cancers correlate with poor clinical outcome? We report that glucocorticoids and mineralocorticoids, in addition to progestins, can stimulate the emergence of CK5+ cells in luminal breast cancer lines in vitro and in vivo. The CK5+ cells showed increased clonogenicity in soft agar, expressed the stem cell marker CD44, frequently lost ER/PR expression, and were enriched following adjuvant antiestrogen or chemotherapies. CK5 expression was preceded by the induction of Bcl6, a transcriptional repressor that has been implicated in breast cancer promotion. Suppression of Bcl6 by lentiviral shRNA delivery, or exposure to the BCL6 suppressor, prolactin, abolished 3–ketosteroid–induction of CK5 expression. Prolactin co-treatment additionally attenuated –ketosteroid–induced colony forming ability and suppressed the induction of progestin–induced CK5+ cells in vivo. Furthermore, increasing levels of CK5 expression was associated with poor clinical outcome in tumors expressing glucocorticoid receptor and progesterone receptor from patients with pre–menopausal breast cancer. Use of glucocorticoids may therefore potentially produce detrimental effects in luminal breast cancer patients, while Bcl6 inhibitors may be explored for therapeutic benefit.^
Subject Area
Biology, Molecular|Health Sciences, Pharmacology|Health Sciences, Oncology
Recommended Citation
Goodman, Chelain Rae, "Induction of a therapy-resistant cytokeratin 5-positive cell population by 3-ketosteroids in luminal breast cancer" (2013). ProQuest ETD Collection - Thomas Jefferson University. AAI3601489.
https://jdc.jefferson.edu/dissertations/AAI3601489
