Hormonal and environmental factors affecting cell proliferation and neoplasia in the mammary gland.

S M Snedeker, R P Diaugustine
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Abstract

Although estrogens have been identified as key endocrine hormones in the control of early mitogenesis and development in the mammary gland, local control of cell proliferation during ductal morphogenesis may be regulated by polypeptides such as TGF-alpha or TGF-beta. Many breast tumors are estrogen dependent, and some breast tumor cell lines are known to produce TGF-alpha, suggesting that the mitogenic pathways controlling early normal mammary growth and the growth of some breast tumors may be similar. While progesterone does not appear to be important in the early program of ductal growth, progesterone and estrogen are necessary for the cyclic proliferation of mammary ductal cells that occurs during the menstrual cycle, and for lobuloalveolar growth during pregnancy. Since increased cell division enhances the chances for the formation of a malignant phenotype in the breast, exogenous hormones containing estrogen alone or estrogen and progesterone may increase breast cancer risk. While DES is no longer prescribed to prevent abortions, it demonstrates that high doses of an estrogen during a period of mammary proliferation can affect breast cancer risk. Whether the addition of progestogens to estrogen replacement therapy enhances breast cancer risk in postmenopausal women remains an unanswered question because of the lack of large, well-controlled prospective studies. There currently is no evidence to indicate that the progestogen-containing subdermal contraceptive Norplant increases breast cancer risk. However, it has not been determined if the elevation of serum estrogens reported in some Norplant users affects breast cancer risk. There is little evidence that combined OCAs enhance breast cancer risk in most women. More research is needed to substantiate the findings that OCA use in young women, especially before a first full-term pregnancy, may enhance breast cancer risk. Animal studies indicate that there are critical periods of susceptibility to chemical carcinogens, since the number and malignancy of tumors are increased when carcinogens are administered to young virgin animals during the proliferative period of ductal morphogenesis. Since the breast appears to be most susceptible to the carcinogenic effects of ionizing radiation during the first decade of life, exposure to other carcinogenic agents during the period of early breast development may be important in determining breast cancer risk. Therefore, more studies are needed to confirm the observation that heavy drinkers and heavy smokers are at higher risk for developing breast cancer when they start smoking or drinking at an early age. The observation that serum and urinary estrogen levels increase with alcohol consumption may provide a basis for the higher risk of developing breast cancer in heavy drinkers. While the restriction of methyxanthine intake may alleviate the symptoms associated with fibrocystic breast disease in some women, there is not enough evidence to suggest that a reduction in caffeine intake will reduce breast cancer risk. Evidence for an association between electromagnetic radiation and breast cancer is limited. Electromagnetic radiation may only pose a risk in certain occupations with exposure to very high levels for extended periods of time. It is not known whether exposure to PCBs transplacentally or though the lipid fraction of human milk can affect breast cancer rates in female offspring. The higher risk of breast cancer in women with elevated DDE levels in their blood underscores the importance of determining the extent to which environmental contaminants affect breast cancer risk.

影响乳腺细胞增殖和肿瘤形成的激素和环境因素。
虽然雌激素已被确定为控制乳腺早期有丝分裂和发育的关键内分泌激素,但导管形态发生过程中细胞增殖的局部控制可能受到tgf - α或tgf - β等多肽的调节。许多乳腺肿瘤依赖雌激素,并且已知一些乳腺肿瘤细胞系产生tgf - α,这表明控制早期正常乳腺生长的有丝分裂途径与某些乳腺肿瘤的生长可能相似。虽然黄体酮在乳腺导管生长的早期过程中似乎并不重要,但黄体酮和雌激素对于月经周期中乳腺导管细胞的循环增殖和怀孕期间小叶肺泡的生长是必需的。由于增加的细胞分裂增加了乳房中形成恶性表型的机会,因此含有单独雌激素或雌激素和黄体酮的外源性激素可能增加乳腺癌的风险。虽然DES不再被用于预防流产,但它表明,在乳房增生期间,高剂量的雌激素会影响患乳腺癌的风险。在雌激素替代疗法中加入孕激素是否会增加绝经后妇女患乳腺癌的风险仍然是一个没有答案的问题,因为缺乏大型的、良好对照的前瞻性研究。目前没有证据表明含孕激素的皮下避孕药Norplant会增加患乳腺癌的风险。然而,还没有确定在一些诺普兰使用者中报告的血清雌激素升高是否会影响乳腺癌的风险。几乎没有证据表明联合服用oca会增加大多数女性患乳腺癌的风险。需要更多的研究来证实年轻女性使用OCA,特别是在第一次足月妊娠之前,可能会增加患乳腺癌的风险。动物研究表明,存在对化学致癌物易感的关键时期,因为在导管形态发生的增殖期给药致癌物会增加肿瘤的数量和恶性程度。由于乳房似乎在生命的头十年最容易受到电离辐射的致癌影响,因此在乳房早期发育期间接触其他致癌物质可能是确定乳腺癌风险的重要因素。因此,需要更多的研究来证实重度饮酒者和重度吸烟者在早期开始吸烟或饮酒时患乳腺癌的风险更高。血清和尿液雌激素水平随饮酒增加的观察结果可能为重度饮酒者患乳腺癌的高风险提供了基础。虽然限制甲黄嘌呤的摄入可能会减轻一些女性纤维囊性乳腺疾病的相关症状,但没有足够的证据表明减少咖啡因的摄入会降低患乳腺癌的风险。电磁辐射与乳腺癌之间的关联证据有限。电磁辐射只有在长时间暴露于极高水平的某些职业中才会造成风险。目前尚不清楚经胎盘接触多氯联苯或人乳中的脂质部分是否会影响女性后代的乳腺癌发病率。血液中DDE水平升高的女性患乳腺癌的风险更高,这凸显了确定环境污染物对乳腺癌风险影响程度的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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