Stathmin 1, a marker of PI3K pathway activation and regulator of microtubule dynamics, is expressed in early pelvic serous carcinomas

Abstract

Background: Most high-grade pelvic serous carcinomas (HGPSCs) arise from fallopian tube epithelium (FTE). To date, few markers have been shown to characterize FTE transformation. Stathmin 1 (STMN1) is a candidate oncogene whose activity is influenced by p53, p27Kip1 (p27), and PI3K/Akt pathway activation. As a microtubule destabilizing protein, STMN1 regulates cytoskeletal dynamics, cell cycle progression, mitosis, and cell migration. This study examines the expression of STMN1 and its negative regulator p27 along the morphologic continuum from normal FTE to invasive carcinoma.

Methods: STMN1 and p27 expression were examined by immunohistochemistry (IHC) in benign (n=12) and malignant (n=13) fallopian tubes containing normal epithelium, morphologically benign putative precursor lesions ("p53 signatures"), potential transitional precursor lesions ("proliferative p53 signatures"), tubal intraepithelial carcinoma (TIC), and/or invasive serous carcinoma. STMN1 expression was further assessed in 131 late-stage HGPSCs diagnosed as primary ovarian and in 6 ovarian cancer cell lines by IHC and Western blot, respectively.

Results: STMN1 expression was absent in benign FTE and infrequently detected in p53 signatures. However, it was weakly expressed in proliferative p53 signatures and robustly induced upon progression to TIC and invasive carcinoma, typically accompanied by decreased p27 levels. STMN1 was expressed in >80% of high-grade serous ovarian carcinomas and cell lines.

Conclusions: STMN1 is a novel marker of early serous carcinoma that may play a role in FTE tumor initiation. Our data are consistent with a model by which STMN1 overexpression, resulting from loss of p27-mediated regulation, may potentiate aberrant cell proliferation, migration, and/or loss of polarity during early tumorigenesis.

Fig. 1

STMN1 expression across the morphologic continuum from benign fallopian tube epithelium to invasive serous carcinoma. (A–D) Histological transition from normal epithelium to benign p53 signature, TIC, and invasive HGPSC. (E–H) Intense nuclear p53 staining characterizes the p53 signature, TIC, and invasive tumor; (I–L) Ki-67 staining identifies proliferating cells in the TIC and invasive tumor; (M–P) STMN1 expression is absent from benign epithelium but is strongly induced upon progression to TIC; (Q-T) p27 expression is frequently lost in STMN1-positive lesions. All images are from one representative case.

Fig. 2

Distribution of STMN1-positive cells in benign and malignant fallopian tube epithelium. STMN1 staining was negative (<10% positive cells) in both normal FTE and most p53 signatures, but positive (10–100%) in proliferative p53 signatures, TIC, and HGPSC.

Fig. 3

STMN1 is expressed in putative HGPSC precursors to HGPSC. A p53 signature (A–E) and proliferative p53 signature (F–J) from the same patient. The p53 signature is non-proliferative, STMN1-negative, and p27 positive. Proliferative p53 signatures are transitional lesions exhibiting features intermediate between a p53 signature and TIC. Here, mildly increased proliferative activity is accompanied by expression of STMN1 and reduced p27.

Fig. 4

Examples of reciprocal STMN1 and p27 expression in TICs. (A -T) Coordinated changes in STMN1 and p27 levels occur at the transitions from benign to malignant epithelium. Note the continuity of STMN1 staining throughout each lesion, even in regions with variable Ki-67 immunoreactivity.

Fig. 5

STMN1 is strongly expressed in serous ovarian carcinomas. (A) In a tissue microarray analysis of 131 high-grade serous ovarian carcinomas, 16% of samples were STMN1-negative [score 0 (all cells negative) or 1+ (<10% positive cells)] while 84% were STMN1-positive [score 2+ (10–75% positive cells) or 3+ (>75% positive cells)]. (B) 5/6 ovarian cancer cell lines express high levels of STMN1 whereas 2 immortalized FTSEC lines are negative, determined by Western blotting. The Müllerian origin of the cell lines was confirmed by PAX8 immunoblotting. GAPDH is a loading control.