人乳腺组织中雌二醇C16α-羟基化上调：乳腺癌风险的潜在生物标志物。

Upregulation of estradiol C16 alpha-hydroxylation in human breast tissue: a potential biomarker of breast cancer risk.

作者信息

Osborne M P, Bradlow H L, Wong G Y, Telang N T

机构信息

Strang-Cornell Cancer Research Laboratory, Strand Cancer Prevention Center, New York, N.Y. 10021.

出版信息

J Natl Cancer Inst. 1993 Dec 1;85(23):1917-20. doi: 10.1093/jnci/85.23.1917.

DOI:10.1093/jnci/85.23.1917

PMID:8230281

Abstract

BACKGROUND

The biotransformation of the natural estrogen 17 beta-estradiol (E2) via the C16 alpha-hydroxylation pathway is elevated in patients with breast cancer, in subjects at increased risk for developing breast cancer, and in c-Ha-ras-initiated mouse mammary epithelial cells.

PURPOSE

To determine whether differences in the extent of E2 C16 alpha-hydroxylation are related to the risk of developing breast cancer, we examined the extent of biotransformation of E2 via the C16 alpha-hydroxylation pathway in the mammary terminal duct lobular units (TDLUs), epithelial organoids that are a presumptive target site of human breast carcinogenesis, and in nontarget component mammary fat tissue.

METHODS

Noninvolved mammary tissue was obtained from four patients undergoing reduction mammoplasty and from four undergoing mastectomy for breast cancer. A radiometric assay that measures 3H2O formation caused by stoichiometric 3H exchange from [C16 alpha-3H]E2 was utilized to compare the relative extent of C16 alpha-hydroxylation in explant cultures of TDLUs and mammary fat.

RESULTS

The extent of E2 C16 alpha-hydroxylation was 1.83-fold higher (95% confidence interval [CI] = 1.71-1.97) in the TDLUs from reduction mammoplasty (i.e., "low-risk") patients and 7.96-fold higher (95% CI = 6.38-10.55) in the TDLUs from mastectomy (i.e., "high-risk") patients than in the corresponding values observed in the mammary fat. In the TDLUs obtained from the patients undergoing mastectomy for cancer, the extent of this metabolism was 4.56-fold higher (95% CI = 3.97-5.33) than that observed in TDLUs obtained from reduction mammoplasty patients who did not have cancer.

CONCLUSION

The increase in the extent of C16 alpha-hydroxylation of E2 in the epithelial organoids of the human breast, TDLUs in particular, may be an important factor for breast cancer induction. This upregulation may represent an endocrine biomarker for the risk of developing breast cancer.

IMPLICATION

A larger prospective study is required to confirm the clinical significance of this endocrine biomarker.

摘要

背景

在乳腺癌患者、乳腺癌发病风险增加的受试者以及c-Ha-ras基因启动的小鼠乳腺上皮细胞中，天然雌激素17β-雌二醇（E2）通过C16α-羟基化途径的生物转化有所增加。

目的

为了确定E2 C16α-羟基化程度的差异是否与患乳腺癌的风险相关，我们检测了E2通过C16α-羟基化途径在乳腺终末导管小叶单位（TDLUs）（一种人类乳腺癌假定靶位点的上皮类器官）和非靶组织成分乳腺脂肪组织中的生物转化程度。

方法

从4例接受缩乳术的患者和4例因乳腺癌接受乳房切除术的患者获取未受累的乳腺组织。采用一种放射性测定法，该方法通过测量由[C16α-3H]E2的化学计量3H交换所导致的3H2O形成，来比较TDLUs和乳腺脂肪外植体培养物中C16α-羟基化的相对程度。

结果

与乳腺脂肪中的相应值相比，接受缩乳术（即“低风险”）患者的TDLUs中E2 C16α-羟基化程度高1.83倍（95%置信区间[CI]=1.71 - 1.97），接受乳房切除术（即“高风险”）患者的TDLUs中高7.96倍（95% CI = 6.38 - 10.55）。在因癌症接受乳房切除术的患者所获取的TDLUs中，这种代谢程度比未患癌症的接受缩乳术患者所获取的TDLUs中高4.56倍（95% CI = 3.97 - 5.33）。