Estrogen and Skin Cancer

描述（由申请人提供）：美国人生活在一种崇尚青春的文化中。据市场研究机构FIND/SVP称，抗衰老产品市场预计到2007年将达到560亿美元。对绝经后妇女的研究发现，激素替代疗法可以有效地扭转影响皮肤老化的干燥和皱纹。基于这些研究，人们越来越关注使用含有雌激素等激素的外用面霜来预防或逆转年轻的绝经前妇女的一些正常皮肤老化过程。虽然暴露在这些面霜中可能对美容有益，但长时间在暴露在阳光下的部位使用雌激素对皮肤癌发展的影响尚不清楚。我们对雌性Skh-1无毛小鼠进行的初步研究发现，在UVB暴露后立即局部接受雌激素治疗的小鼠肿瘤数量明显高于对照组。这些数据表明，皮肤中雌激素水平的增加加上紫外线暴露可能会加强紫外线诱发皮肤癌的发生和促进。这些发现还表明，年轻女性在暴露在阳光下的部位使用含有雌激素化合物的乳液和面霜，可能会导致40岁以下女性被诊断出皮肤肿瘤的数量增加。大多数研究都调查了局部或全身雌激素对绝经后妇女皮肤的影响，但事实是，年轻的绝经前妇女正在将含有局部雌激素的面霜涂抹在之前暴露在紫外线下的脸上，以防止/逆转衰老的迹象。我们提出了两个具体的目的来验证局部雌激素应用于以前暴露于UVB的皮肤加速皮肤癌发生的假设。具体目标1的研究将使用UVB诱导皮肤癌变的Skh-1无毛小鼠模型，以确定临床使用的局部应用雌激素（Estrogel(R)）对UVB诱导的皮肤肿瘤发展的影响，这些肿瘤发生在先前暴露于UVB的完整（绝经前）和卵巢切除（绝经后）的雌性小鼠皮肤上。特定目标2的研究将确定局部应用雌激素（Estrogel(R)）对UVB诱导的完整和去卵巢小鼠雌性Skh-1皮肤肿瘤进展的影响。这些研究的目的是确定局部雌激素是否会增加UVB诱导的皮肤肿瘤的发生数量，以及它是否会不同程度地促进良性UVB诱导的肿瘤向恶性鳞状细胞癌的发展（绝经前和卵巢切除后）小鼠。

DESCRIPTION (provided by applicant): Americans live in a culture that glorifies youth. According to market researcher FIND/SVP, the anti- aging products market is expected to hit $56 billion by 2007. Studies in post-menopausal women have found that hormone replacement therapy is effective at reversing the dryness and wrinkling that affects aging skin. Based on these studies, there is increasing interest in the use of topical creams containing hormones such as estrogen to prevent or reverse some of the normal cutaneous aging processes in younger pre-menopausal women. While exposure to these creams may be beneficial cosmetically, the effect of applying estrogen to sun exposed sites for prolonged periods of time, on skin cancer development is not known. Our preliminary studies using female Skh-1 hairless mice found a significant increase in the number of tumors in mice treated topically with estrogen immediately following UVB exposure compared to mice treated with vehicle control. These data indicate that increased levels of estrogen in the skin combined with UV exposure may act to enhance initiation and promotion of UV-induced skin cancers. These findings also suggest that the use of lotions and creams containing estrogenic compounds on sun exposed sites by younger women may be contributing to the increase in the number of skin tumors being diagnosed in women under the age of 40. Most studies have examined the effects of topical or systemic estrogen on the skin in post-menopausal women, however the reality is that younger pre-menopausal women are applying topical estrogen containing creams on their faces previously exposed to UV light to prevent/reverse the signs of aging. Two specific aims are proposed to test the hypothesis that topical estrogen application to previously UVB exposed skin accelerates skin carcinogenesis. Studies in specific aim 1 will use the Skh-1 hairless mouse murine model of UVB induced skin carcinogenesis to determine the effects of clinically used topically applied estrogen (Estrogel(R)) on UVB induced skin tumor development in previously UVB exposed female skin of intact (pre-menopausal) and ovariectomized (post-menopausal) mice. Studies in specific aim 2 will determine the effects of topically applied estrogen (Estrogel(R)) on UVB induced skin tumor progression in female Skh-1 skin of intact and ovariectomized mice. The studies carried out in these aims will determine whether topical estrogen increases the number of UVB induced skin tumors that develop and also whether it differentially enhances the progression of benign UVB-induced tumors to malignant squamous cell carcinomas in intact (pre-menopausal) and ovariectomized (post-menopausal) mice. PUBLIC HEALTH RELEVANCE: There is an increase societal pressure in the US to remain young looking. Several studies carried out in post-menopausal women demonstrate the effectiveness of topical estrogen in reversing the signs of aging including thinning, dryness and wrinkling. As a result younger pre- and peri-menopausal women are turning to topical creams containing estrogen as anti-aging lotions. Our preliminary studies using female Skh-1 hairless mice found a significant increase in the number of tumors in mice treated topically with estrogen immediately following UVB exposure compared to mice treated with vehicle control. These data indicate that increased levels of estrogen in the skin combined with UV exposure may act to enhance initiation and promotion of UV- induced skin cancers. These findings also suggest that the use of lotions and creams containing estrogenic compounds on sun exposed sites by younger women may be contributing to the increase in the number of skin tumors being diagnosed in women under the age of 40. The current studies are designed to determine the effect of topical estrogen treatment of previously UVB exposed skin on tumor development and progression from benign lesions to frank malignant squamous cell carcinomas.