Gutzman Jennifer H, Miller Kristin K, Schuler Linda A
Department of Comparative Biosciences, 2015 Linden Drive, University of Wisconsin-Madison, Madison, WI 53706, USA.
J Steroid Biochem Mol Biol. 2004 Jan;88(1):69-77. doi: 10.1016/j.jsbmb.2003.10.008.
Prolactin (PRL) and estrogen act synergistically to increase mammary gland growth, development, and differentiation. Based on their roles in the normal gland, these hormones have been studied to determine their interactions in the development and progression of breast cancer. However, most studies have evaluated only endocrine PRL and did not take into account the recent discovery that PRL is synthesized by human mammary cells, permitting autocrine/paracrine activity. To examine the effects of this endogenous PRL, we engineered MCF7 cells to inducibly overexpress human prolactin (hPRL). Using this Tet-On MCF7hPRL cell line, we studied effects on cell growth, PRLR, ER alpha, and PgR levels, and estrogen target genes. Induced endogenous hPRL, but not exogenous hPRL, increased ER alpha levels as well as estrogen responsiveness in these cells, suggesting that effects on breast cancer development and progression by estrogen may be amplified by cross-regulation of ER alpha levels by endogenous hPRL. The long PRLR isoform was also upregulated by endogenous, but not exogenous PRL. This model will allow investigation of endogenous hPRL in mammary epithelial cells and will enable further dissection of PRL effects on other hormone signaling pathways to determine the role of PRL in breast cancer.
催乳素（PRL）和雌激素协同作用，促进乳腺生长、发育和分化。基于它们在正常腺体中的作用，人们对这些激素进行了研究，以确定它们在乳腺癌发生和发展过程中的相互作用。然而，大多数研究仅评估了内分泌型PRL，并未考虑到最近发现的人乳腺细胞能合成PRL，从而产生自分泌/旁分泌活性这一情况。为了研究这种内源性PRL的作用，我们构建了可诱导性过表达人催乳素（hPRL）的MCF7细胞。利用这种Tet-On MCF7hPRL细胞系，我们研究了其对细胞生长、PRLR、雌激素受体α（ERα）、孕激素受体（PgR）水平以及雌激素靶基因的影响。诱导产生的内源性hPRL而非外源性hPRL，增加了这些细胞中的ERα水平以及雌激素反应性，这表明内源性hPRL通过对ERα水平的交叉调节，可能会放大雌激素对乳腺癌发生和发展的影响。长型PRLR异构体也受到内源性PRL而非外源性PRL的上调。该模型将有助于研究乳腺上皮细胞中的内源性hPRL，并能进一步剖析PRL对其他激素信号通路的影响，以确定PRL在乳腺癌中的作用。
