Abstract
The microtubule-stabilizing agent docetaxel in combination with gemcitabine represents one of the most effective regimens against the aggressive gynecologic tumor leiomyosarcoma (LMS). Upregulation of class III β-tubulin has previously been shown to confer taxane resistance in a variety of human cancers. Prostaglandin E2 receptor EP4 is linked to progression of a variety of human cancers and may represent a novel target for tumor inhibition in LMS. We evaluated the hypotheses that EP4 and class III β-tubulin have increased expression in LMS in comparison to normal myometrium or benign tumors and that expression of class III β-tubulin correlates with resistance to taxanes and poor clinical outcome. Gene expression was examined using TCGA data and correlated with clinicopathologic outcome which demonstrated that class III β-tubulin is more highly expressed in more aggressive sarcomas with EP4 being widely expressed in all subtypes of sarcoma. Immunohistochemistry for EP4 and class III β-tubulin was performed on patients with LMS, leiomyomatosis/STUMP, leiomyoma, and normal myometrium. Expression of EP4 and class III β-tubulin were characterized for cell lines SK-UT-1, SK-UT-1B, and PHM-41 and these cell lines were treated with docetaxel alone and in combination with EP4 inhibitors. In taxane-resistant cell lines that overexpress class III β-tubulin and EP4, treatment with EP4 inhibitor resulted in at least 2-fold sensitization to docetaxel. Expression of class III β-tubulin and EP4 in LMS may identify patients at risk of resistance to standard chemotherapies and candidates for augmentation of therapy through EP4 inhibition.
Highlights
In 2019, approximately 61,880 women in the United States will be diagnosed with a malignancy of the uterine corpus
Given the results from the theobtained cancer genome atlascancer (TCGA) analysis, we identified a total of 29 cases of uterine smooth muscle tumors from our institution in order to analyze protein expression of class III β-tubulin and
We have shown that LMS cell lines have increased expression of both EP4 and class III β-tubulin compared to normal myometrium and the expression and location
Summary
In 2019, approximately 61,880 women in the United States will be diagnosed with a malignancy of the uterine corpus. 12,160 die from their disease annually [1]. Cancers 2019, 11, 1590 represent a minority (8%) of these cases but carry a disproportionately poor prognosis across all stages. Leiomyosarcoma (LMS) is the most common uterine sarcoma, representing 40–60% of cases [2]. Development of effective novel therapeutic approaches requires a more thorough understanding of sarcoma tumor biology. The microtubule component β-tubulin is potentially expressed as nine isoforms. Expression of the constitutive form (class I) is ubiquitous, whereas class III β-tubulin is generally restricted to normal neural tissues [4].
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