Abstract 4213: Evaluation of LMTK3 expression and tumor phenotype in estrogen-dependent colorectal cancer

Abstract

Abstract Background: Incompatible physiology between genders influences development and progression of colorectal cancer (CRC). It is postulated that improved survival of women with CRC may be due to exogenous estrogen exposure. A recent study used the age of 50 as a surrogate for menopause, evaluating survival in two age groups: women ≥50 and ≤50. It was observed that women ≤50 had a survival advantage that was contributed to protection by estrogen- a mechanism lost in menopause; with no significant difference found in men. Lemur tyrosine kinase 3 (LMTK3) was recently identified, that when in association with an estrogen receptor (ER) α modulator increased growth, progression, and altered resistance to endocrine therapy was observed in breast cancer. The ER family (ERα and ERβ) exerts contrasting actions of estrogen on different target tissues, where ERβ is the dominant receptor expressed in the gastrointestinal tract. The different ER distribution between breast and colon cancer led to the hypothesis that LMTK3 overexpression should stabilize ERβ and decrease tumorigenesis in CRC. Methods: CRC cell lines were characterized for LMTK3 mRNA (qRT-PCR) and protein expression (Western blot) in both transfected and non-transfected cell lines. Overexpression of LMTK3 was achieved utilizing pCMV6-XL4-LMTK3. Overexpressing LMTK3 CRC cells were evaluated for alterations to cell viability by MTT, colony formation (CFAs), invasion assays and chemosensitivity to 5-Fluororuacil, oxaliplatin, and tamoxifen. Results: CRC cell lines demonstrated a range of LMTK3, ERα and ERβ mRNA and protein expression. Caco-2, HCT116 and LoVo cells demonstrated estrogen sensitivity as evidenced by treatment with ER antagonist, tamoxifen. CFA demonstrated that the presence of estrogen plus overexpression of LMTK3 decreased cell viability by 27, 28 and 36% in Caco2, HCT116 and LoVo cells respectively, had limited impact on chemosensitivity, and decreased their ability to invade. Conclusion: This study demonstrates that estrogen mediated cell signaling and LMTK3 play an important role in decreasing CRC tumorigenesis. Further studies are underway to better understand estrogen and LMTK3's role in CRC. Citation Format: Sybil Magturo, Georgios Giamas, Snay Mallick, Austin Layton, Justin Stebbing, Heinz-Josef Lenz, Melissa J. LaBonte. Evaluation of LMTK3 expression and tumor phenotype in estrogen-dependent colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4213. doi:10.1158/1538-7445.AM2014-4213