Progestin treatment decreases CD133+ cancer stem cell populations in endometrial cancer

Gynecol Oncol. 2016 Mar;140(3):518-26. doi: 10.1016/j.ygyno.2015.12.022. Epub 2015 Dec 28.

Abstract

Objectives: Endometrial cancer is a hormonally responsive malignancy. Response to progestins is associated with estrogen receptor (ER) and progesterone receptor (PR) status. CD133 is a marker of endometrial cancer stem cells. We postulated that CD133+ cells express ER and PR and that progestin therapy differentially regulates CD133+ cells.

Methods: The Ishikawa (ER/PR positive) and KLE (ER/PR negative) cell lines were examined for the presence of CD133 populations. Cell lines were treated with 30.4μM medroxyprogesterone 17-acetate (MPA) for 6days. After treatment, cell counts, apoptosis assays and CD133+ populations were examined. In a clinical project, we identified 12 endometrial cancer patients who were treated with progestin drugs at our institution. Using immunohistochemistry, CD133, ER, PR, and androgen receptor (AR) expression was scored and evaluated for change over time on serial biopsies.

Results: CD133+ populations were identified in Ishikawa and KLE cell lines. MPA treatment resulted in a significant reduction in the percentage of live cells (Ishikawa, P=0.036; KLE, P=0.0002), significant increase in apoptosis (Ishikawa, P=0.01; KLE, P=0.0006) and significant decrease in CD133+ populations (Ishikawa, P<0.0001; KLE, P=0.0001). ER, PR, AR and CD133 were present in 96.4%, 96.4%, 89.3% and 100% of patient samples respectively. Paralleling the in vitro results, CD133 expression decreased in patients who had histologic response to progestin treatment.

Conclusion: CD133+ populations decreased after treatment with MPA in an in vitro model and in patients responding to treatment with progestins. Progestin treatment differentially decreases CD133+ cells.

Keywords: Cancer stem cells; Endometrial cancer; Hormonal treatment; Progesterone; Progestin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / metabolism*
  • Adult
  • Aged
  • Antigens, CD* / metabolism
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Apoptosis / drug effects
  • Cell Count
  • Cell Line, Tumor
  • Endometrial Neoplasms / drug therapy*
  • Endometrial Neoplasms / metabolism*
  • Female
  • Glycoproteins* / metabolism
  • Humans
  • Medroxyprogesterone Acetate / pharmacology*
  • Medroxyprogesterone Acetate / therapeutic use
  • Middle Aged
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Peptides* / metabolism
  • Receptors, Androgen / metabolism
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism

Substances

  • AC133 Antigen
  • Antigens, CD
  • Antineoplastic Agents, Hormonal
  • Glycoproteins
  • PROM1 protein, human
  • Peptides
  • Receptors, Androgen
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Medroxyprogesterone Acetate