Stathmin 1, a Marker of PI3K Pathway Activation and Regulator of Microtubule Dynamics, Is Expressed in Early Serous Ovarian Carcinomas.
Alison M Karst, Keren Levanon, Sekhar Duraisamy, Joyce F Liu, Michelle S Hirsch, Ronny Drapkin. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Sheba Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan, Israel; Brigham and Women's Hospital, Boston, MA
Background: The fallopian tube secretory epithelial cell (FTSEC) is the likely cell of origin for most high-grade pelvic serous carcinomas, including serous ovarian carcinoma. Studies of serous tumor precursor lesions in fallopian tube epithelium demonstrate that TP53 mutations and accumulation of DNA damage play critical roles in FTSEC transformation. However, few other markers characterize the progression from benign to malignant fallopian tube mucosa. Here, we identify Stathmin 1 (STMN1) as a novel marker of FTSEC transformation. STMN1 is a microtubule destabilizing protein that regulates cytoskeletal dynamics, cell cycle progression, mitosis, and cell migration. Its activity is strongly linked to the activation of growth and differentiation signalling pathways.
Design: We used immunohistochemistry to assess STMN1 and p27Kip1 expression in a panel of benign (n = 13) and malignant (n = 12) fallopian tubes containing normal epithelium, p53 signatures, tubal intraepithelial carcinoma, and invasive serous carcinoma. We further examined STMN1 expression in 131 high-grade late-stage serous ovarian carcinomas by tissue microarray analysis and a panel of ovarian cancer cell lines by Western blot.
Results: STMN1 was expressed in neither quiescent cells nor benign lesions of the fallopian tube epithelium, but was robustly induced with progression to tubal intraepithelial carcinoma. STMN1 induction during early tumorigenesis was accompanied by decreased p27Kip1 expression, a negative regulator of G0- to S-phase transition and direct inhibitor of STMN1. STMN1 was expressed in > 80% of high-grade serous ovarian carcinomas and ovarian cancer cell lines, indicating that expression is retained in late disease stages. Additionally, STMN1 may be a useful proliferative cell marker, independent of MIB1.
Conclusions: The dynamics of STMN1 expression observed in early tubal lesions suggest that STMN1 plays a critical role in FTSEC cell cycle progression. Its induction in benign-appearing cells may signal cell cycle entry and identify pre-mitotic cells with proliferative potential. STMN1 expression might contribute to HGPSC pathogenesis by relaying growth signals from oncogenic signal transduction pathways to the cytoskeleton or by potentiating early-stage cell migration and loss of polarity.
Category: Gynecologic & Obstetrics
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 95, Tuesday Afternoon