Oestrogen increases S-phase fraction and oestrogen and progesterone receptors in human cervical cancer in vivo

Abstract

Summary Although cancer of the cervix is traditionally considered not to be responsive to steroid hormones, an in vitro study has reported that the addition of oestrogen increased cellular proliferation in a cervix cancer cell line that was inhibited by progesterone. We investigated whether the reported in vitro effects of oestrogen and progesterone on cellular proliferation can be replicated in locally advanced cervical cancer in vivo and whether these effects, if any, are related to oestrogen and progesterone receptor (ER and PgR) content of the tumour. One hundred post-menopausal patients with locally advanced cervical cancer were systematically allocated by rotation to the four treatment groups: (1) control group receiving no treatment; (2) ethinyl oestradiol 50 gg; (3) norethisterone 5 mg; (4) a combination of ethinyl oestradiol and norethisterone. Hormone treatment (five doses) was given orally every 12 h. Tissue biopsies were taken before and 12 h after the last hormone treatment. S-phase fraction (SpF) was measured by flow cytometry, and ER and PgR were measured by enzyme immunoassay. Results were analysed using two-factor analysis of variance, the factors being oestrogen -absent or present -and progesterone -absent or present. The main effects of oestrogen were increases in SpF, ER and PgR, which were statistically significant (P= 0.0056, 0.0009 and 0.01 respectively), indicating that there is much greater change in these three parameters in the presence of oestrogen (mean changes 7.808 %, 6.258 fmol mg-' and 12.716 fmol mg-' for SpF, ER and PgR respectively) than in its absence (mean change -1.986 %, -3.041 fmol mg-' and 1.736 fmol mg-' respectively). The progestogen main effect and the oestrogen -progestogen interaction were not significant. The rise in SpF, ER and PgR in the presence of oestrogen had a correlation coefficient with the initial ER values of -0.0565, -0.2863 and -0.1230 respectively, none being statistically significant, suggesting that the oestrogen actions were not strictly related to baseline ER concentrations. The combined median baseline ER and PgR values of the four groups were 1.48 fmol mg-' and 0.80 fmol mg-' respectively. Our results show that oestrogen is capable of increasing SpF in locally advanced cervical cancer in vivo and may help to revive interest in the use of oestrogen as a radiosensitizing agent in the treatment of this disease.Keywords: cervical cancer; S-phase fraction; oestrogen receptor; progesterone receptor; radiosensitisation Carcinoma of the cervix is the commonest cancer in women in the developing world where most patients present at advanced stages when treatment with radiotherapy is not very effective (Hoskins et al, 1993). At least two studies have used adjuvant oestrogen treatment in an attempt to increase sensitivity of squamous cell carcinoma of the cervix to radiation therapy (Runge, 1959;Sugimori et al, 1976). One of these studies reported a significantly better survival in stage III patients in whom oestrogen was administered before and during radi...

Risk Factors for Cervical Cancer in Northeastern Thailand: Detailed Analyses of Sexual and Smoking Behavior

“…First, co-factors may promote HPV infection by causing cervical epithelial injury, such as: early age at first sexual activity and first delivery, multiple pregnancies and/or multiple sexual partners (Kahn et (Delvenne et al, 2007), leading to increased risk for cervical cancer in longer use of contraceptive in this study. Estrogen contained in oral contraceptives may affect cervical carcinogenesis in several ways, such as: increasing the S-phase fraction (Bhattacharya et al, 1997), increasing the sensitivity of cervical transformation zone (Hughes et al, 1988;Castellsague et al, 2003) and binding to a specific DNA sequences within transcriptional regulatory regions on the HPV DNA either to increase or to suppress transcription of various genes (Moodley et al, 2003). On the other hand, long-term consumption of oral contraceptives among women may reflect potentially frequent sexual activity, which may also increase the risk of contracting HPV or other sexually-transmitted diseases.…”

Organization of Human Papillomavirus Productive Cycle during Neoplastic Progression Provides a Basis for Selection of Diagnostic Markers

“…Most cervical intraepithelial lesions originate from cells in the transformation zone, the region of cervical epithelium that changes from columnar to squamous in response to hormonal changes such as those occurring at puberty or during pregnancy. This region of the cervix is particularly sensitive to estrogen (1) and to estrogen-induced carcinogenesis (29), and the prolonged use of estrogen-containing oral contraceptives has been reported to double the incidence of cervical cancer (9) and affect the level of viral gene expression in vivo (6,59) and in vitro (10,50,61). Although the effect of hormones on late gene expression has not yet been characterized, it is clear from the data presented here that the timing, but not the order, of late events changes in a marked but predictable way during the progression from CIN1 to CIN3.…”

“…The probes were then used separately to identify the specific infecting HPV type. In some instances, typing was carried out using a smaller selection of probes, consisting of HPV types 6,11,16,18,31,33,35,42,43,44,45,52,56, and 58 (n ϭ 5). A small number of cases (n ϭ 3) were screened for the presence of active HPV16 infection by immunostaining using antibodies to the HPV16 E4 protein.…”

In Silicoanalysis of perturbed steroidogenesis and gonad growth in fathead minnows (P. promelas) exposed to 17α-ethynylestradiol

“…The mechanism of such inhibition is purported to be via the activation of the estrogen receptor (ER) signaling pathways in the hypothalamus, which in turn trigger feedback-inhibition of gonadotropin release [Herbison and [Bhattacharya et al 1997], with the propensity to bind and activate various human ER isoforms such as ERa and ERb [Zhu et al 2006]. EE2 affinity for ERs also lends to promiscuity of binding to ERs in other vertebrate species, such as rats and fish [Blair et al 2000;Le Guevel and Pakdel 2001].…”