Estrogen and Skin Cancer

描述(由申请人提供)：美国人生活在一种崇尚年轻人的文化中。根据市场研究机构Find/SVP的数据，到2007年，抗衰老产品市场预计将达到560亿美元。对绝经后女性的研究发现，激素替代疗法在逆转影响皮肤老化的干燥和皱纹方面有效。基于这些研究，越来越多的人对使用含有雌激素等激素的外用面霜来预防或逆转年轻绝经前女性的一些正常皮肤衰老过程感兴趣。虽然接触这些面霜可能对美容有益，但长期将雌激素应用于暴露在阳光下的部位对皮肤癌的影响尚不清楚。我们使用雌性SKH-1无毛小鼠进行的初步研究发现，与使用赋形剂对照的小鼠相比，在UVB照射后立即局部使用雌激素的小鼠的肿瘤数量显着增加。这些数据表明，皮肤中雌激素水平的增加与紫外线暴露相结合，可能会增强紫外线诱导皮肤癌的启动和促进作用。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，可能是导致40岁以下女性被诊断为皮肤肿瘤数量增加的原因之一。大多数研究都考察了局部或全身雌激素对绝经后女性皮肤的影响，然而现实是，更年轻的绝经前女性正在将含有雌激素的局部乳膏涂在先前暴露在紫外线下的面部，以防止/扭转衰老迹象。有两个特定的目标被提出来检验这一假说，即在以前暴露于UVB的皮肤上应用局部雌激素会加速皮肤癌的发生。针对特定目的1的研究将利用UVB诱导的皮肤癌变的SKH-1无毛小鼠模型来确定临床使用的局部应用雌激素(EstroGel(R))对UVB先前暴露的完整(绝经前)和卵巢切除(绝经后)小鼠的女性皮肤中UVB诱导的皮肤肿瘤的影响。针对特定目标2的研究将确定局部应用雌激素(EstroGel(R))对UVB诱导的完整和卵巢切除小鼠的雌性SKH-1皮肤肿瘤进展的影响。在这些目标下进行的研究将确定局部雌激素是否增加UVB诱导的皮肤肿瘤的发展数量，以及它是否在不同程度上促进完整(绝经前)和去卵巢(绝经后)小鼠的良性UVB诱导的肿瘤向恶性鳞状细胞癌的进展。 与公共健康相关：在美国，保持年轻形象的社会压力越来越大。在绝经后妇女身上进行的几项研究表明，外用雌激素在逆转衰老迹象方面的有效性，包括变瘦、干燥和皱纹。因此，年轻的绝经前和围绝经期女性开始使用含有雌激素的外用乳膏作为抗衰老乳液。我们使用雌性SKH-1无毛小鼠进行的初步研究发现，与使用赋形剂对照的小鼠相比，在UVB照射后立即局部使用雌激素的小鼠的肿瘤数量显着增加。这些数据表明，皮肤中雌激素水平的增加与紫外线暴露相结合，可能会增强紫外线诱导皮肤癌的启动和促进作用。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，可能是导致40岁以下女性被诊断为皮肤肿瘤数量增加的原因之一。目前的研究旨在确定局部雌激素治疗对先前UVB暴露的皮肤的肿瘤发展和从良性病变到直接恶性鳞癌的进展的影响。

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.