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Date of release: 11 February, 2009

HRT and colorectal cancer


A recently published paper has evaluated colorectal cancer risk associated with the duration and recency of specific menopausal hormone therapy formulations viz. unopposed estrogen versus estrogen combined with continuously or sequentially administered progestin among 56,733 postmenopausal women participating in the Breast Cancer Detection Demonstration Project (BCDDP) follow-up study [1]. There were 960 women who were identified to have developed colorectal cancer over a mean follow-up period of 15 years and mean age at commencement of follow-up of 55.7 years. Current use of estrogen (relative risk (RR), 0.75; 95% confidence interval (CI), 0.54–1.05) and duration of use of > 10 years (RR, 0.74; 95% CI, 0.56–0.96) were associated with the largest reduction of risk compared to non-users. Estrogen with sequentially administered progestin for < 15 days per cycle (RR, 0.64; 95% CI, 0.43–0.95) was more protective than continuous combined estrogen and progestin therapy.

Comment

Carcinogenesis is a complex and multi-step process that involves a number of genes. The interaction with environmental insults will ultimately result in dysregulation of cell proliferation.
This is relevant since this important long-term follow-up report confirms many previous observational data but is at variance with results of the Women’s Health Initiative (WHI) unopposed conjugated equine estrogen (CEE) study [2]. To be precise, even the WHI conjugated equine estrogens plus medroxyprogesterone acetate (CEE + MPA) trial did not show a statistically significant drop in the incidence of colon cancer, since the range of the adjusted hazard ratio was 0.63 (95% CI 0.32–1.24) [3]. As such, both WHI reports of CEE + MPA and unopposed CEE therapy addressed preventative effects of gonadal steroids among a group of women two-thirds of whom were older than 60 years of age and 73.9% and 52.2%, respectively, were never users of hormonal supplement [2,3]. As such, cumulative carcinogenetic events would have already developed and, with the short duration of the trial, a non-significant impact of hormonal treatment was reported. Consequently, despite being randomized controlled trials, the relevance of the WHI results is questionable.
In order to accept epidemiological data, their biological plausibility is fundamental in understanding the significance of these data and their applicability in clinical settings. While the authors of the BCDDP have referred to literature on the biological correlates of colorectal cancer, it appeared only in the context of administration of exogenous gonadal steroids.
An important clinical feature of women treated with estrogen and progestin is that they have retained their ovaries until natural menopause and therefore benefited from the protective effects of their endogenous estrogen for longer than women who have used unopposed estrogen. Nonetheless, the steroidogenic actions within cells are more complex than the interactions of ligands with their cognate receptors. Conversion of androstenedione into testosterone and inter-conversions of estrone to estradiol are governed by 17β-hydroxysteroid dehydrogenase (17βHSD). The enzyme 17βHSD and its at least six iso-enzymes are differentially expressed in various tissues and 17βHSD iso-enzyme types 2 and 4 are over-expressed in colonic cancer cells. This may be responsible for the high capacity for inactivation of estrogens in colon cancer cells [4,5]. This local conversion to estrogens may play a role in the non-receptor-mediated effect of estrogen in the pathophysiology of cell growth. These data illustrate clearly a cell context-specific concentration of these gonadal steroids.
Estradiol induces the synthesis of its cognate receptors and the synthesis of progesterone receptors. Progesterone, upon binding its cognate receptors, down-regulates the synthesis of its own receptors as well as estrogen receptors, and progesterone increases the activity of 17β-hydroxyl and therefore counteracts estrogen activity. Characteristics of colon cancer tissue included loss of immunohistochemical expression of estrogen receptor (ER)-α protein [6] and very low levels of ER-α protein in Western blot analysis.  These are combined with a selective loss of ER-β protein expression being detected, in males and in females, when compared to the normal colon tissue in the same patient [7]. All these findings point to impairment of the post-transcriptional mechanism upon malignant transformation of colon tissue that suggests loss of estrogen effects, when compared to normal colon tissue. Estrogen acts either on a single major transformation step in the oncogenetic process or is involved in multiple events that avert the course of this transformation.
Aggregates of cytosine (C) and guanosine (G) are found in the promoter regions of many genes and are referred to as CpG islands. Normally, the CpG islands in the promoter regions of genes are free of methylation. DNA methylation has emerged as a robust mechanism of perpetuating epigenetic changes in gene expression through mitosis [8]. Methylation of the CpG islands is equivalent to the silencing of that gene, with the consequence of inactivation, or reduced expression, of a number of genes downstream.
Partial methylation of the estrogen receptor CpG (ERCpG) island is reported in normal colonic mucosa and increases with age, but, in colonic cancer tissue, complete methylation occurs [9]. It is concluded that methylation of the CpG island acts as a transcriptional silencing mechanism of a tumor suppressor gene, and this may be one of the earliest molecular mechanisms involved in colonic neoplasia. ERCpG island methylation is found to be associated with suppression of p53 (as well as other similar genes such as retinoblastoma RB gene, p16, and c-myc expression) [10].
Activation of the ER gene may involve other genes that influence cellular differentiation, such as the induction of vitamin D receptors (VDR). Vitamin D2 (1,25-dihydroxy vitamin D) and several of its analogs are potent antineoplastic agents in many cell types, including colon-derived cells. Estrogen administration is associated with reduced methylation of the VDR gene and with upregulation of both VDR gene transcription and protein expression. It is concluded that estrogen may interfere with the process of CpG DNA methylation in the colonic mucosa to prevent silencing of the VDR gene [11]. Whether VDR activity is one of the mechanisms by which estrogen protects against neoplastic transformation in the colon remains to be seen.
‘A window of opportunity’ does probably exist for maximum benefits of estrogen against colorectal cancer, as has been proposed for cardiovascular diseases, where estrogen administration early in the menopause has proved protective. Many women as well as prescribers remain uncertain regarding the far-reaching benefits of delaying the impact of estrogen deficiency. A great deal of work is required to amend the confusion caused by the uncritical publications of the WHI data.

Comentario

Farook Al-Azzawi
Menopause Research Unit, University Hospitals of Leicester, Leicester, UK

    References

  1. Johnson JR, Lacey JV Jr, Lazovich D, et al. Menopausal hormone therapy and risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 2009;18:196-203. Published January 2009.
    http://www.ncbi.nlm.nih.gov/pubmed/19124498

  2. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Womens Health Initiative randomized controlled trial. JAMA 2004;291:1701-12.
    http://www.ncbi.nlm.nih.gov/pubmed/15082697

  3. Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 2004;350:991-1004.
    http://www.ncbi.nlm.nih.gov/pubmed/14999111

  4. English MA, Kane KF, Cruickshank N, Langman MJ, Stewart PM, Hewison M. Loss of estrogen inactivation in colonic cancer. J Clin Endocrinol Metab 1999;84:2080-5.
    http://www.ncbi.nlm.nih.gov/pubmed/10372714

  5. English MA, Hughes SV, Kane KF, Langman MJ, Stewart PM, Hewison M. Oestrogen inactivation in the colon: analysis of the expression and regulation of 17beta-hydroxysteroid dehydrogenase isozymes in normal colon and colonic cancer. Br J Cancer 2000;83:550-8.
    http://www.ncbi.nlm.nih.gov/pubmed/10945506

  6. Slattery ML, Samowitz WS, Holden JA. Estrogen and progesterone receptors in colon tumors. Am J Clin Pathol 2000;113:364-8.
    http://www.ncbi.nlm.nih.gov/pubmed/10705816

  7. Foley EF, Jazaeri AA, Shupnik MA, Jazaeri O, Rice LW. Selective loss of estrogen receptor beta in malignant human colon. Cancer Res 2000;60:245-8.
    http://www.ncbi.nlm.nih.gov/pubmed/10667568

  8. Cedar H. DNA methylation and gene activity. Cell 1988;53:3-4.
    http://www.ncbi.nlm.nih.gov/pubmed/3280142

  9. Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB. Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 1994;7:536-40.
    http://www.ncbi.nlm.nih.gov/pubmed/7951326

  10. Horvath G, Leser G, Karlsson L, Delle U. Estradiol regulates tumor growth by influencing p53 and bcl-2 expression in human endometrial adenocarcinomas grown in nude mice. In Vivo 1996;10:411-16.
    http://www.ncbi.nlm.nih.gov/pubmed/8839787

  11. Jiang SY, Jordan VC. Growth regulation of estrogen receptor-negative breast cancer cells transfected with complementary DNAs for estrogen receptor. J Natl Cancer Inst 1992;84:580-91.
    http://www.ncbi.nlm.nih.gov/pubmed/1556769