Significance of intratissue estrogen concentration coupled with estrogen receptors levels in colorectal cancer prognosis

Rawłuszko-Wieczorek, Agnieszka Anna; Marczak, Łukasz; Horst, Nikodem; Horbacka, Karolina; Krokowicz, Piotr; Jagodzińśki, Paweł P.

doi:10.18632/oncotarget.23309

Cited by 12 publications

(6 citation statements)

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“…In contrast, elevated systemic testosterone levels and higher expression of ERα and AR proteins in CRC were associated with larger tumours, poor differentiation, advanced clinical stages, and worse outcomes in both genders ( 15 , 26 – 28 ). Hence, our data and results from prior reports ( 14 – 16 , 19 , 28 , 45 , 46 ) suggest that testosterone with AR and ERα could promote CRC development, while E2 and P4, alongside ERβ and PGR, may act as tumour suppressors.…”

Section: Discussionsupporting

confidence: 71%

“…In agreement with our results, the risk of CRC increased by > 20% following oophorectomy and the odds augmented substantially with bilateral rather than unilateral ovariectomy ( 45 , 46 ). Moreover, higher serum levels of female reproductive steroid hormones alongside increased expression of ERβ and/or PGR in malignant tissues correlated with better prognosis in male and female CRC patients ( 14 , 16 – 19 ). In contrast, elevated systemic testosterone levels and higher expression of ERα and AR proteins in CRC were associated with larger tumours, poor differentiation, advanced clinical stages, and worse outcomes in both genders ( 15 , 26 – 28 ).…”

Section: Discussionmentioning

confidence: 97%

“…Additionally, normal colonic epithelium can generate and respond to sex steroid hormones, since enterocytes express the synthesising enzymes of 17β-oestradiol (E2), P4, and testosterone alongside their nuclear receptors (ERα, ERβ, PGR and AR) ( 12 – 15 ). Serum concentrations of E2 and/or P4 also correlated with significantly better prognosis in CRC patients, independent of their sex ( 14 , 16 – 19 ). In vitro and in vivo experimental studies have likewise demonstrated suppression of cell proliferation and survival following treatment with E2 and P4 by ERβ and/or PGR-mediated anti-cancer activities ( 18 – 25 ).…”

Section: Introductionmentioning

confidence: 89%

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Enhanced anti-cancer effects of oestrogen and progesterone co-therapy against colorectal cancer in males

et al. 2022

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Although ovarian sex steroids could have protective roles against colorectal cancer (CRC) in women, little is currently known about their potential anti-tumorigenic effects in men. Hence, this study measured the therapeutic effects of 17β-oestradiol (E2) and/or progesterone (P4) against azoxymethane-induced CRC in male mice that were divided into (n = 10 mice/group): negative (NC) and positive (PC) controls, E2 (580 µg/Kg/day; five times/week) and P4 (2.9 mg/Kg/day; five times/week) monotherapies, and concurrent (EP) and sequential (E/P) co-therapy groups. Both hormones were injected intraperitoneally to the designated groups for four consecutive weeks. Similar treatment protocols with E2 (10 nM) and/or P4 (20 nM) were also used in the SW480 and SW620 human male CRC cell lines. The PC group showed abundant colonic tumours alongside increased colonic tissue testosterone levels and androgen (AR) and oestrogen (ERα) receptors, whereas E2 and P4 levels with ERβ and progesterone receptor (PGR) decreased significantly compared with the NC group. E2 and P4 monotherapies equally increased ERβ/PGR with p21/Cytochrome-C/Caspase-3, reduced testosterone levels, inhibited ERα/AR and CCND1/survivin and promoted apoptosis relative to the PC group. Both co-therapy protocols also revealed better anti-cancer effects with enhanced modulation of colonic sex steroid hormones and their receptors, with E/P the most prominent protocol. In vitro, E/P regimen showed the highest increases in the numbers of SW480 (2.1-fold) and SW620 (3.5-fold) cells in Sub-G1 phase of cell cycle. The E/P co-therapy also disclosed the lowest percentages of viable SW480 cells (2.8-fold), whilst both co-therapy protocols equally showed the greatest SW620 apoptotic cell numbers (5.2-fold) relative to untreated cells. Moreover, both co-therapy regimens revealed maximal inhibitions of cell cycle inducers, cell survival markers, and AR/ERα alongside the highest expression of cell cycle suppressors, pro-apoptotic molecules, and ERβ/PGR in both cell lines. In conclusion, CRC was associated with abnormal levels of colonic sex steroid hormones alongside aberrant protein expression of their receptors. While the anti-cancer effects of E2 and P4 monotherapies were equal, their combination protocols showed boosted tumoricidal actions against CRC in males, possibly by promoting ERβ and PGR-mediated androgen deprivation together with inhibition of ERα-regulated oncogenic pathways.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 89%

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Enhanced anti-cancer effects of oestrogen and progesterone co-therapy against colorectal cancer in males

et al. 2022

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“…We observed that these groups had a higher CRC incidence rate. This finding is similar to a previous study that reported an association between the dysregulation of estrogen-related pathways and CRC development [44], and that estrogen-related gene polymorphisms were positively correlated with CRC risk [45,46]. Overexpression of HSD17B4 has been observed in various cancers, including prostate cancer [47], hepatocellular carcinoma [48], and breast cancer [49].…”

Section: Discussionsupporting

confidence: 91%

Susceptibility to Colorectal Cancer Based on HSD17B4 rs721673 and rs721675 Polymorphisms and Alcohol Intake among Taiwan Biobank Participants: A Retrospective Case Control Study Using the Nationwide Claims Data

Lin

Chuang

Hsiung

et al. 2023

JPM

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Colorectal cancer (CRC) is a major public health issue, and there are limited studies on the association between 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4) polymorphism and CRC. We used two national databases from Taiwan to examine whether HSD17B4 rs721673, rs721675, and alcohol intake were independently and interactively correlated with CRC development. We linked the Taiwan Biobank (TWB) participants’ health and lifestyle information and genotypic data from 2012 to 2018 to the National Health Insurance Database (NHIRD) to confirm their medical records. We performed a genome-wide association study (GWAS) using data from 145 new incident CRC cases and matched 1316 healthy, non-CRC individuals. We calculated the odds ratios (OR) and 95% confidence intervals (CI) for CRC based on multiple logistic regression analyses. HSD17B4 rs721673 and rs721675 on chromosome 5 were significantly and positively correlated with CRC (rs721673 A > G, aOR = 2.62, p = 2.90 × 10−8; rs721675 A > T, aOR = 2.61, p = 1.01 × 10−6). Within the high-risk genotypes, significantly higher ORs were observed among the alcohol intake group. Our results demonstrated that the rs721673 and rs721675 risk genotypes of HSD17B4 might increase the risk of CRC development in Taiwanese adults, especially those with alcohol consumption habits.

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“…Steroid sulfatase promotes the synthesis of E1, whereas estrogen sulfotransferase inactivates E1 thus supporting a prognostic role for these enzymes and E1 in CRC. However, another study failed to find significant correlation between tumoral tissue concentrations of estrogen and CRC survival ( 43 ). Instead patients with low intra-tissue concentration of estrone coupled with low estrogen receptor ESR1 expression showed increased CRC recurrence compared to patients with high ESR1 mRNA levels and high E1 concentration.…”

Section: Sexual Dimorphism Of Hormones and Receptors In Crcmentioning

confidence: 99%

Sexual Dimorphism in Colon Cancer

et al. 2020

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A higher incidence of colorectal cancer (CRC) is found in males compared to females. Young women (18–44 years) with CRC have a better survival outcome compared to men of the same age or compared to older women (over 50 years), indicating a global incidence of sexual dimorphism in CRC rates and survival. This suggests a protective role for the sex steroid hormone estrogen in CRC development. Key proliferative pathways in CRC tumorigenesis exhibit sexual dimorphism, which confer better survival in females through estrogen regulated genes and cell signaling. Estrogen regulates the activity of a class of Kv channels (KCNQ1:KCNE3), which control fundamental ion transport functions of the colon and epithelial mesenchymal transition through bi-directional interactions with the Wnt/β-catenin signalling pathway. Estrogen also modulates CRC proliferative responses in hypoxia via the novel membrane estrogen receptor GPER and HIF1A and VEGF signaling. Here we critically review recent clinical and molecular insights into sexual dimorphism of CRC biology modulated by the tumor microenvironment, estrogen, Wnt/β-catenin signalling, ion channels, and X-linked genes.

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Significance of intratissue estrogen concentration coupled with estrogen receptors levels in colorectal cancer prognosis

Cited by 12 publications

References 50 publications

Enhanced anti-cancer effects of oestrogen and progesterone co-therapy against colorectal cancer in males

Enhanced anti-cancer effects of oestrogen and progesterone co-therapy against colorectal cancer in males

Susceptibility to Colorectal Cancer Based on HSD17B4 rs721673 and rs721675 Polymorphisms and Alcohol Intake among Taiwan Biobank Participants: A Retrospective Case Control Study Using the Nationwide Claims Data

Sexual Dimorphism in Colon Cancer

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