Cause or prevention of breast cancer with estrogens: analysis from tumor biologic data, growth kinetic model and Women’s Health Initiative study

Abstract

The existing medical literature suggests that estrogens may cause breast cancer but, paradoxically, can also prevent this neoplasm under specific circumstances. Appropriate interpretation of this complex data requires an understanding of emerging concepts of tumor biology. A substantial body of data, including animal models and epidemiologic studies, suggests that estrogens contribute to the development of breast cancer. Additionally, pre-clinical experiments indicate that the responsible mechanisms include both estrogen receptor α-dependent and -independent effects (ERα-dependent and ERα-independent effects). We recently developed two models to describe the growth kinetics of occult breast tumors, one based on autopsy studies and tumor doubling time and the other, computer-based. Validation of the models involved comparison of the predicted incidence of breast cancer with the actual incidence in population-based studies. Utilization of these models allowed us to determine that 16 years on average are required for tumors to undergo the 30 doubling times necessary for the occult tumors to reach the threshold for clinical detection. These models suggest that menopausal hormone therapy with estrogen plus a progestogen in the Women’s Health Initiative (WHI) study accelerated the doubling time of occult, pre-existing tumors from 200 to 150 days and thus, increased the rate of tumor diagnosis. Based on estrogen-induced apoptosis data, the model accurately predicted the prevention of diagnosed breast cancer in the estrogen-alone arm of the WHI. Notably, pre-clinical studies demonstrated that conjugated equine estrogen, as used in the WHI, has unique, pro-apoptotic properties compared to the anti-apoptotic effects of estradiol, a finding providing an explanation for the reduction in breast cancer with conjugated equine estrogen.

Chinese abstract

现有的医学文献表明, 雌激素可能会导致乳腺癌, 但矛盾的是, 在特定情况下也可预防这种癌症。对这一复杂情况的恰当解释需要了解肿瘤生物学的新概念。大量数据, 包括动物模型和流行病学研究显示, 雌激素引起乳腺癌的发展。此外, 临床前实验提示, 其机制包括雌激素受体α依赖性和非依赖性效应（ERα依赖性和ERα非依赖性效应）。我们近期开发了两个模型来描述隐匿性乳腺肿瘤的生长动力学, 一个基于尸检研究和肿瘤倍增时间, 另一个模型基于计算机。模型的验证包括乳腺癌预测发病率和基于人群研究中的实际发病率之间的比较。利用这些模型, 我们可以确定肿瘤平均需要16年, 才能使隐匿性肿瘤达到临床检测阈值需要30倍倍增时间。这些模型提示妇女健康倡议（WHI）研究中, 采用雌激素加孕激素进行绝经后激素治疗使隐匿地、预先存在的肿瘤的倍增时间从200天加速至150天, 提高了肿瘤诊断率。基于雌激素诱导的凋亡数据, 该模型准确地预测了WHI研究单雌激素组对乳腺癌的预防作用。值得注意的是, 临床前研究证实, 与雌二醇的抗凋亡作用相比, WHI研究中马结合雌激素有独特的促凋亡特性, 这一发现为结合马雌激素降低乳腺癌风险提供了解释。

Keywords:

• Tumor kinetics
• detection threshold
• effective doubling time
• de novo tumor
• occult tumor

Additional information

Funding

Nil.