Polymorphic CAG Repeat and Protein Expression of Androgen Receptor Gene in Colorectal Cancer

Huang, Rui; Wang, Guiyu; Song, Yanni; Wang, Feng; Zhu, Bing; Tang, Qingchao; Liu, Zheng; Chen, Yinggang; Zhang, Qian; Muhammad, Shan; Wang, Xishan

doi:10.1158/1535-7163.mct-14-0620

Cited by 28 publications

(22 citation statements)

References 24 publications

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“…24 Moreover, a case-control study showed that the CRC cases group had a longer cytosine-adenine-guanine (CAG) repeat length in the androgen receptor gene in comparison to controls in both males and females. 25 While another study has reported no association between the lengths of CAG repeats in the androgen receptor and CRC. 26 Testosterone may promote development of CRC via several possible pathways; however, further studies focusing on female populations are required to explain the possible role of testosterone in CRC tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Male rats who underwent orchidectomy and administered with testosterone were more susceptible to tumor load compared to placebos . Moreover, a case–control study showed that the CRC cases group had a longer cytosine–adenine–guanine (CAG) repeat length in the androgen receptor gene in comparison to controls in both males and females . While another study has reported no association between the lengths of CAG repeats in the androgen receptor and CRC .…”

Section: Discussionmentioning

confidence: 99%

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Circulating sex hormone levels and colorectal cancer risk in Japanese postmenopausal women: The JPHC nested case–control study

Mori¹,

Sawada²,

Iwasaki³

et al. 2019

Intl Journal of Cancer

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Previous epidemiological studies evaluated endogenous sex hormone levels and colorectal cancer (CRC) risk have yielded inconsistent results. Also, it is unknown if consumption of dietary isoflavones may influence the endogenous sex hormones and CRC relationships. We conducted a nested case–control study within the JPHC Study Cohort II wherein 11,644 women provided blood samples at the 5‐year follow‐up survey. We selected two matched controls for each case from the cohort (185 CRC cases and 361 controls). Multivariable conditional logistic regression was used to estimate odds ratios (ORs), 95% confidence intervals (CIs) for the association between circulating sex hormone levels and CRC risk. Comparing extreme tertiles, circulating testosterone levels were positively associated with CRC risk (OR = 2.10, 95% CI = 1.11–3.99, p for trend = 0.03). Levels of estradiol, SHBG, and progesterone were not associated with CRC risk. In a subgroup analysis by dietary isoflavone intake, SHBG levels were positively associated with CRC risk among those with low total isoflavone intake (p for trend = 0.03), with a statistically nonsignificant inverse association among those with high total isoflavone intake (p for trend = 0.22; p for interaction = 0.002). Endogenous levels of testosterone were positively associated with CRC among postmenopausal women. The association of endogenous SHBG with CRC development may be altered by the level of dietary isoflavone intake.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Circulating sex hormone levels and colorectal cancer risk in Japanese postmenopausal women: The JPHC nested case–control study

Mori¹,

Sawada²,

Iwasaki³

et al. 2019

Intl Journal of Cancer

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“…Breast cancer tissue microarrays (TMA) were used as described previously [23, 24] and immunohistochemically stained for AR, ER, PR, Her2, Ki67 and β-catenin expression levels. Briefly, after deparaffinization, sections were hydrated and underwent Ethylene Diamine Tetraacetic Acid (EDTA) buffer (pH 8.0) or sodium citrate buffer (pH 6.0) retrieval.…”

Section: Methodsmentioning

confidence: 99%

Androgen Receptor Expression and Bicalutamide Antagonize Androgen Receptor Inhibit β-Catenin Transcription Complex in Estrogen Receptor-Negative Breast Cancer

Huang

Han

Liang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Little is known about the potential mechanism of action for androgen receptor (AR) targeting treatment in estrogen receptor (ER)-negative breast cancer. This study aimed to evaluate AR status and its prognosis in four breast cancer subtypes. Bicalutamide has been identified as an AR antagonist and used for treating AR+/ER- breast cancer in a phase II trial. Our studies will clarify its mechanism in breast cancer treatment. Methods: A total of 510 consecutive cases of invasive ductal cancer (IDC) were evaluated in this study. The expression of AR was analyzed by immunohistochemistry and compared with patient survival, and its implications were evaluated in four subtypes of IDC. We examined bicalutamide as an AR antagonist to inhibit proliferation and increased apoptosis in AR+/ER- breast cancer cell lines. We explored the tumor suppressive functions of bicalutamide in vitro and vivo and its related mechanisms in AR+/ER- breast cancer. Results: AR expression was related to that of ER (P<0.001), PR (P<0.001), Her2 (P=0.017), Ki-67(P=0.020) and to four subtypes (P<0.001). AR retained independent prognostic signifcance (P=0.007, ER- cases; P=0.001, ER+ cases; P=0.001, total cases). We found that bicalutamide significantly decreased viability and increased apoptosis in vitro and vivo. The mechanistic analysis revealed that bicalutamide blocked androgen-stimulated oncogenic AR and Wnt/β-catenin signaling and inhibited the growth of AR+/ER- breast cancer. Conclusion: Our studies provide novel insights into bicalutamide as an antagonist of AR function in AR+/ER- breast cancer and reveal the mechanistic basis for targeting AR as a therapeutic opportunity for patients with AR+/ER- breast cancer.

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“…These CAG can alter the function of the AR gene. A case-control study investigating the effect of this polymorphism on CRC risk was carried out on 550 CRC cases and 540 healthy controls, who were analysed for presence of CAG sequences in the AR gene using polymerase chain reaction (PCR) [43]. The study showed that the CRC group had a longer CAG repeat length compared to the control group and that this repeat confers an increased risk of developing CRC in both males and females, whereas a shorter CAG repeat size may protect individuals against CRC.…”

Section: Role Of Testosterone In Colorectal Carcinomamentioning

confidence: 99%

“…In addition, the absence of AR expression in long CAG repeat sequences was associated with tumour size larger than 5 cm in diameter, which were moderate to poorly differentiated (at T3–T4 and N1–2 stages) compared to those with normal expression of AR and short CAG repeat sequences. Aside from the link to tumour stage, these patients were also reported to have a poor survival rate even after postoperative adjuvant chemotherapy as they demonstrated greater risk of recurrence or metastasis [43]. On the contrary, a different study has reported that there is no association between the length of CAG repeats in the AR and colorectal cancer.…”

Section: Role Of Testosterone In Colorectal Carcinomamentioning

confidence: 99%

The role of testosterone in colorectal carcinoma: pathomechanisms and open questions

2016

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Colorectal cancer (CRC) is the fourth commonest type of malignancy after breast, lung and prostate in the USA and accounts for approximately 49,190 deaths annually in USA alone. The 5-year survival rate of CRC has increased over the past decades, in part, due to greater awareness and the widespread implementation of national screening programmes. Recently, a number of studies reported that males have a higher risk of developing CRC due to the action of testosterone.Testosterone is an androgen that is responsible for the development of male secondary sex characteristics and for spermatogenesis. Studies on rats with mutated Apc tumour-suppressor gene subjected to either ovariectomy or orchidectomy exhibit different risks of CRC. Female rats subjected to ovariectomy are at higher risk of CRC, whereas orchidectomised male rats exhibit a lower risk of developing CRC. Sex hormones, in particular estrogen and testosterone, play a significant role in the development of CRC since the anti-neoplastic effect of estrogen lost during ovariectomy increases the risk of females developing CRC. Male mice exposed to testosterone after orchidectomy were also at greater risk than those who were orchidectomised but administered placebo only. Moreover, the recently established role of membrane androgen receptors in regression of CRC via non-genomic androgen-dependent action sets these receptors apart from intracellular androgen receptors (iARs) which themselves promote CRC development. In addition, testosterone-albumin conjugates are selective to membrane androgen receptors (mARs) and lead to apoptosis via caspase-3 activation. Akt kinases promote invasion of colon cancer cells when phosphorylated. These kinases are dephosphorylated upon activation of mARs, thereby reducing colon cancer cell motility and invasiveness.Testosterone similarly plays important roles in human CRC. Long cytosine-adenine-guanine (CAG) repeats in the gene for the androgen receptors have been associated with a poor 5-year survival compared to shorter CAG repeats. Very recently, the measurement of serum unbound testosterone has been suggested as a novel biomarker along with carcinoembryonic antigen in CRC. In conclusion, testosterone may promote the development of CRC via a number of pathways, which may place males at greater risk. Testosterone holds promise as a potential biomarker in CRC risk prediction; however, further studies are required to better define its role in colorectal neoplasia.

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Polymorphic CAG Repeat and Protein Expression of Androgen Receptor Gene in Colorectal Cancer

Cited by 28 publications

References 24 publications

Circulating sex hormone levels and colorectal cancer risk in Japanese postmenopausal women: The JPHC nested case–control study

Circulating sex hormone levels and colorectal cancer risk in Japanese postmenopausal women: The JPHC nested case–control study

Androgen Receptor Expression and Bicalutamide Antagonize Androgen Receptor Inhibit β-Catenin Transcription Complex in Estrogen Receptor-Negative Breast Cancer

The role of testosterone in colorectal carcinoma: pathomechanisms and open questions

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