Mutation or Loss of p53 Differentially Modifies TGFβ Action in Ovarian Cancer

Abstract

Ovarian cancer is the most lethal gynecological disease affecting women in the US. The Cancer Genome Atlas Network identified p53 mutations in 96% of high-grade serous ovarian carcinomas, demonstrating its critical role. Additionally, the Transforming Growth Factor Beta (TGFβ) pathway is dysfunctional in various malignancies, including ovarian cancer. This study investigated how expression of wild-type, mutant, or the absence of p53 alters ovarian cancer cell response to TGFβ signaling, as well as the response of the ovarian surface epithelium and the fallopian tube epithelium to TGFβ. Only ovarian cancer cells expressing wild-type p53 were growth inhibited by TGFβ, while ovarian cancer cells that were mutant or null p53 were not. TGFβ induced migration in p53 null SKOV3 cells, which was not observed in SKOV3 cells with stable expression of mutant p53 R273H. Knockdown of wild-type p53 in the OVCA 420 ovarian cancer cells enhanced cell migration in response to TGFβ. Increased protein expression of DKK1 and TMEPAI, two pro-invasive genes with enhanced expression in late stage metastatic ovarian cancer, was observed in p53 knockdown and null cells, while cells stably expressing mutant p53 demonstrated lower DKK1 and TMEPAI induction. Expression of mutant p53 or loss of p53 permit continued proliferation of ovarian cancer cell lines in the presence of TGFβ; however, cells expressing mutant p53 exhibit reduced migration and decreased protein levels of DKK1 and TMEPAI.

Activin A stimulates migration of the fallopian tube epithelium, an origin of high-grade serous ovarian cancer, through non-canonical signaling

“…Activin A was also unable to inhibit proliferation of MOE cells in the presence of 10% FBS (Figure S1), which agrees with our previous study showing that TGFβ1 or SB431542 (activin and TGFβ inhibitor) had no effect on proliferation of murine FTE in a 3D culture system [49]. These results suggest that the TGFβ superfamily does not similarly regulate proliferation of the FTE and OSE [50].…”

“…In agreement, neither TGFβ1 nor SB431542 had any effect on proliferation in a 3D model of the mouse FTE [49]. In contrast, activin A and TGFβ have repeatedly been shown to inhibit proliferation of OSE cells [49,50], and in vivo deletion of Smad3 resulted in increased proliferation of OSE [67]. The role of activin A and TGFβ in ovarian cancer cell lines is mixed.…”

“…It is also possible that the response of cells is dependent on changes that occur during transformation. For example, proliferation in response to TGFβ has been linked to p53 signaling [49], and p53 is mutated in almost all cases of HGSOC [69]. …”

Phase II Trial of Chemopreventive Effects of Levonorgestrel on Ovarian and Fallopian Tube Epithelium in Women at High Risk for Ovarian Cancer: An NRG Oncology Group/GOG Study

“…It has been shown, for example, that expression of Bcl-2, an antiapoptotic protein, is increased in ovaries and fallopian tubes of women at increased risk of ovarian cancer, thereby potentially rendering these organs more resistant to apoptosis (30). In addition, mutation or loss of p53 expression, as commonly occurs in high-risk fallopian tubes, may blunt responsiveness to TGFb (31). (iii) The chemopreventive effect of progestins may be due to effects unrelated to apoptosis or TGFb signaling.…”

Switching Roles of TGF-β in Cancer Development: Implications for Therapeutic Target and Biomarker Studies

“…A possible mechanism of this inhibition is that p53 regulates the expression of EMT mediator- Zeb1/2 and stem cell executor- BMI1 through transcriptional activation of miR-200c [37], which is also a downstream target of the TGF-β signaling pathway [38,39,40]. Meanwhile, expression of mutant p53 (R273H) or loss of p53 inhibits the suppressive function of TGF-β in cell proliferation in an ovarian cancer cell line [41]. An important study which was conducted in lung cancer cell line H1299 and ovarian cancer cell line SKOV3 showed that cells expressing mutant p53 lost their sensitivity to TGF-β.…”