Estrous Cycle Modulates Ovarian Carcinoma Growth

Abstract

Purpose: The effects of reproductive hormones on ovarian cancer growth are not well understood. Here, we examined the effects of estrous cycle variation and specific reproductive hormones on ovarian cancer growth. Experimental Design: We investigated the role of reproductive hormones in ovarian cancer growth using both in vivo and in vitro models of tumor growth. Results: In vivo experiments using the HeyA8 and SKOV3ip1 ovarian cancer models showed that tumor cell inoculation during proestrus significantly increased tumor burden (251-273%) compared with injection during the estrus phase. Treatment of ovariectomized mice with 17h-estradiol resulted in a 404% to 483% increase in tumor growth compared with controls. Progestins had no significant effect, but did block estrogen-stimulated tumor growth. Tumors collected from mice sacrificed during proestrus showed increased levels of vascular endothelial growth factor (VEGF) and microvessel density compared with mice injected during estrus. HeyA8, SKOV3ip1, and mouse endothelial (MOEC) cells expressed estrogen receptor a and h and progesterone receptor at the protein and mRNA levels, whereas 2774 ovarian cancer cells were estrogen receptor^negative. In vitro assays showed that 17h-estradiol significantly increased ovarian cancer cell adhesion to collagen in estrogen receptor^positive, but not in estrogen receptor^negative cells. Additionally, 17h-estradiol increased the migratory potential of MOEC cells, which was abrogated by the mitogen-activated protein kinase (MAPK) inhibitor, PD 09859. Treatment with 17h-estradiol activated MAPK in MOEC cells, but not in HeyA8 or SKOV3ip1cells. Conclusion: Our data suggest that estrogen may promote in vivo ovarian cancer growth, both directly and indirectly, by making the tumor microenvironment more conducive for cancer growth.

Estrogen receptor expression and increased risk of lymphovascular space invasion in high-grade serous ovarian carcinoma

“…These findings support the recent population-based study and other meta-analyses that imply prognostic impact of estrogen as a pro-oncogenic factor in ovarian cancer [10,13]. Molecularly, our data also support previous pre-clinical data that showed that the mechanisms of tumor progression in women with estrogen exposure occur as a result of direct tumor growth via VEGF induction and indirect growth via MAPK signaling in the tumor microenvironment [15][16][17][18]. However, a recent study including 1,742 women with HGSOC did not find that estrogen receptor expression itself was a significant predictor of survival [8].…”

“…In particular, this increased risk of ovarian cancer with estrogen use was seen for serous histology [13,14]. Mechanistically, two molecular pathways have been proposed to explain ovarian cancer growth, metastasis, and progression related to estrogen: (i) tumor production of vascular endothelial growth factor (VEGF) via estrogen receptor signaling (direct pathway); and (ii) increased tumor-endothelial cell migration via mitogen-activated protein kinases (MAPK) signaling (in direct pathway) [15][16][17][18]. In contrast, a recent large-size multicenter consortium study concluded that estrogen receptor expression in HGSOC did not impact survival outcomes [8].…”

Estrogen receptor expression and increased risk of lymphovascular space invasion in high-grade serous ovarian carcinoma

“…These findings support the recent population-based study and other meta-analyses that imply prognostic impact of estrogen as a pro-oncogenic factor in ovarian cancer [10,13]. Molecularly, our data also support previous pre-clinical data that showed that the mechanisms of tumor progression in women with estrogen exposure occur as a result of direct tumor growth via VEGF induction and indirect growth via MAPK signaling in the tumor microenvironment [15-18]. However, a recent study including 1,742 women with HGSOC did not find that estrogen receptor expression itself was a significant predictor of survival [8].…”

“…In particular, this increased risk of ovarian cancer with estrogen use was seen for serous histology [13,14]. Mechanistically, two molecular pathways have been proposed to explain ovarian cancer growth, metastasis, and progression related to estrogen: (i) tumor production of vascular endothelial growth factor (VEGF) via estrogen receptor signaling (direct pathway); and (ii) increased tumor-endothelial cell migration via mitogen-activated protein kinases (MAPK) signaling (in direct pathway) [15-18]. In contrast, a recent large-size multicenter consortium study concluded that estrogen receptor expression in HGSOC did not impact survival outcomes [8].…”

Activation of estrogen receptor α by estradiol and cisplatin induces platinum-resistance in ovarian cancer cells

“…These results are consistent with other reports, which suggest that E2 bound ERa induced cell proliferation via activation of ERK and Akt. [12][13][14]32 Cisplatin induces activation of the ERK and Akt cascades, which promote cell survival and correlate with platinum resistance. 33 However, it was not previously known that cisplatin activates ERa in ovarian cancer cells.…”