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. 2017 Jan 10;8(2):2372-2380.
doi: 10.18632/oncotarget.13676.

Recurrence of cervical cancer and its resistance to progestin therapy in a mouse model

Fabiola F Mehta  1 , Seunghan Baik  1 , Sang-Hyuk Chung  1
Affiliations

Recurrence of cervical cancer and its resistance to progestin therapy in a mouse model (V体育安卓版)

VSports - Fabiola F Mehta et al. Oncotarget. .

Abstract

Studies using K14E6/K14E7 transgenic mice expressing E6 and E7 oncoprotein of human papillomavirus type 16 (HPV16) have demonstrated that estrogen (E2) is required for the genesis and growth of cervical cancer. Our prior study using the same mouse model has showed that progestin drug medroxyprogesterone acetate (MPA) promotes regression of primary cervical cancer. In the present study, we use the same transgenic mouse model to determine whether the cancer recurs after MPA therapy. Cervical cancer recurred even if MPA treatment was continued. Unlike primary cervical cancer, the cancer recurred even in the absence of exogenous E2 when MPA treatment was ceased VSports手机版. Furthermore, recurrent cervical cancer did not fully regress upon MPA treatment. Our results support that MPA fails to completely eliminate primary cervical cancer cells and that remaining cancer cells grow independent of exogenous E2 and are refractory to MPA. .

Keywords: cervical cancer; human papillomavirus (HPV); medroxyprogesterone acetate (MPA); recurrence; therapy resistance. V体育安卓版.

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Conflict of interest statement

CONFLICTS OF INTEREST

Authors have nothing to disclose.

Figures

Figure 1
Figure 1. Cervical cancer recurs after MPA therapy
(A) Treatment regimens are depicted. K14E6/K14E7 mice were enrolled at 4−6 weeks of age. MPA, medroxyprogesterone acetate; E2, estrogen. (B) Shown are representative images of H&E−stained cervical epithelium from indicated groups. Scale bar, 50 μm. (C) Shown are representative images of H&E−stained cervical cancer from indicated groups. Scale bar, 50 μm.
Figure 2
Figure 2. Exogenous E2 results in larger recurrent cervical cancer without affecting proliferation and apoptosis
(A) Exogenous E2 does not increase the number of recurrent cervical cancer. The number of cancer in each mouse is shown as box plot. Red lines show the medians and box limits indicate the 25th and 75th percentiles. Whiskers extend 1.5 times the interquartile range. A dot indicates outlier. Group sizes are indicated in Table 1. Rec., recurrence. (B) Exogenous E2 increases total invasion area. Total invasion area per mouse is shown as box plot as described in A. Group sizes are indicated in Table 1. *P = 0.01, **P = 0.05, ***P = 0.03. (C) Exogenous E2 induces larger recurrent cervical cancer. The size of largest cancer per mouse is shown as box plot as described in A. Group sizes are indicated in Table 1. *P = 0.02, **P = 0.05. (D) Exogenous E2 or MPA does not affect proliferation of recurring cervical cancer cells. Cervical cancer sections were stained for BrdU (green) to measure cell proliferation. Nuclei are shown in blue. Dotted lines separate cervical cancer (cc) from stroma (st). Scale bar, 50 μm. (E) Results shown in D. was quantified and shown as mean ± S.E.M. (n = 3). (F) Exogenous E2 or MPA does not influence apoptosis of recurrent cervical cancer. Cervical cancer sections were subjected to TUNEL assay. TUNEL+ cells are shown in green (see white arrows). Nuclei are shown in blue. Scale bar, 30 μm. (G) Results shown in F. was quantified and shown as mean ± S.E.M. (n = 3).
Figure 3
Figure 3. MPA fails to regress recurrent cervical cancer
(A) Treatment regimens are shown. Mice were enrolled in the study at 4−6 weeks of age. (B) Recurrent cervical cancer remains after MPA therapy. Representative images of H&E−stained cervical tissue sections are shown. The number of mice with presented histology is indicated at the upper left corner. Black arrows point to cells with clear cytoplasm, indicative of mucinification. Scale bar, 50 μm. (C) K10 expression is decreased in recurrent cervical cancer treated with MPA. Cervical cancer sections were stained for K10 (green) and K14 (red). K14 stains cancer cells and K10 is a marker for differentiated squamous cells. Nuclei are shown in blue. Dotted lines separate cervical cancer (cc) from stroma (st). Scale bar, 50 μm.
Figure 4
Figure 4. MPA decreases the size of recurrent cervical cancer by inhibiting proliferation
(A) MPA does not decrease multiplicity of recurrent cervical cancer. The number of recurrent cervical cancer per mouse is shown in box plot. Outliers are represented by dots. Control, n = 5; recurrence (rec.) therapy, n = 6. (B) MPA decreases total invasion area. Total invasion area per mouse is shown in box plot. *P = 0.04 (n = 5 for control; n = 6 for recurrence therapy). (C) MPA decreases the size of largest cancer. Largest cancer size per mouse is shown in box plot. *P = 0.03 (n = 5 for control; n = 6 for recurrence therapy). (D) MPA decreases cell proliferation in recurrent cervical cancer. Cervical cancer sections were stained for BrdU (green). Nuclei are shown in blue. Dotted lines separate cancer (cc) from stroma (st). Scale bar, 50 μm. (E) Quantification of results shown in D. is shown as mean ± S.E.M. (n = 3). *P = 0.05. (F) MPA does not influence apoptosis of cancer cells. Cervical cancer sections were subjected to TUNEL assay. TUNEL+ cells are shown in green (see white arrows). Nuclei are shown in blue. Scale bar, 50 μm. (G) Quantification of results shown in F. is shown as mean ± S.E.M. (n = 3).
Figure 5
Figure 5. PR, ERα, and MCM7 are expressed in recurrent cervical cancer
(A) Cancer recurrence and MPA resistance are not due to loss of PR expression. Seven cervical cancers per group were stained for PR (red) and representative images are shown. Nuclei are shown in blue. A cervical cancer section from K14E7/Pgr−/− (PRKO) was used as negative control. Dotted lines separate cervical cancer (cc) from surrounding stroma (st). Note that PR is expressed in recurrence (rec.) therapy and prevention group. Scale bar, 50 μm. (B) ERα expression is similar in all cancers. Seven cervical cancers per group were stained for ERα (green) and representative images are shown. Nuclei are shown in blue. A cervical tissue section from Esr1−/− (ERαKO) was used as negative control. Dotted lines separate cervical cancer (cc) or epithelium (ep) from stroma (st). Scale bar, 50 μm. (C) MCM7 expression is similar in all cancers. Seven cervical cancers per group were stained for MCM7 (red), marker for E7 function and representative images are shown. Nuclei are shown in blue. Normal mouse IgG was used as negative control. Dotted lines separate cervical cancer (cc) from surrounding stroma (st). Scale bar, 30 μm.
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