Department of Comparative Biosciences, University of Wisconsin-Madison, 2015 Linden Dr., Madison, WI 53706, USA.
Breast Cancer Res. 2011 Jan 28;13(1):R11. doi: 10.1186/bcr2819.
Tumors that express estrogen receptor alpha (ERα+) comprise 75% of breast cancers in women. While treatments directed against this receptor have successfully lowered mortality rates, many primary tumors initially or later exhibit resistance. The paucity of murine models of this "luminal" tumor subtype has hindered studies of factors that promote their pathogenesis and modulate responsiveness to estrogen-directed therapeutics. Since epidemiologic studies closely link prolactin and the development of ERα+ tumors in women, we examined characteristics of the aggressive ERα+ and ERα- carcinomas which develop in response to mammary prolactin in a murine transgenic model (neu-related lipocalin- prolactin (NRL-PRL)). To evaluate their relationship to clinical tumors, we determined phenotypic relationships among these carcinomas, other murine models of breast cancer, and features of luminal tumors in women.
We examined a panel of prolactin-induced tumors for characteristics relevant to clinical tumors: histotype, ERα/progesterone receptor (PR) expression and estrogen responsiveness, Activating Protein 1 (AP-1) components, and phosphorylation of signal transducer and activator of transcription 5 (Stat5), extracellular signal regulated kinase (ERK) 1/2 and AKT. We compared levels of transcripts in the ERα-associated "luminal" signature that defines this subtype of tumors in women and transcripts enriched in various mammary epithelial lineages to other well-studied genetically modified murine models of breast cancer. Finally, we used microarray analyses to compare prolactin-induced ERα+ and ERα- tumors, and examined responsiveness to estrogen and the anti-estrogen, Faslodex, in vivo.
Prolactin-induced carcinomas were markedly diverse with respect to histotype, ERα/PR expression, and activated signaling cascades. They constituted a heterogeneous, but distinct group of murine mammary tumors, with molecular features of the luminal subtype of human breast cancer. In contrast to morphologically normal and hyperplastic structures in NRL-PRL females, carcinomas were insensitive to ERα-mediated signals. These tumors were distinct from mouse mammary tumor virus (MMTV)-neu tumors, and contained elevated transcripts for factors associated with luminal/alveolar expansion and differentiation, suggesting that they arose from physiologic targets of prolactin. These features were shared by ERα+ and ERα- tumors, suggesting a common origin, although the former exhibited transcript profiles reflecting greater differentiation.
Our studies demonstrate that prolactin can promote diverse carcinomas in mice, many of which resemble luminal breast cancers, providing a novel experimental model to examine the pathogenesis, progression and treatment responsiveness of this tumor subtype.
表达雌激素受体 alpha（ERα+）的肿瘤占女性乳腺癌的 75%。虽然针对该受体的治疗方法已成功降低了死亡率，但许多原发性肿瘤最初或后来表现出耐药性。缺乏这种“腔隙”肿瘤亚型的小鼠模型阻碍了对促进其发病机制和调节对雌激素导向治疗反应的因素的研究。由于流行病学研究将催乳素与女性 ERα+肿瘤的发展密切相关，因此我们研究了在小鼠转基因模型（神经相关脂联素-催乳素（NRL-PRL））中对催乳素反应而发展的侵袭性 ERα+和 ERα-癌的特征。为了评估它们与临床肿瘤的关系，我们确定了这些癌之间的表型关系，其他乳腺癌的小鼠模型以及女性腔隙肿瘤的特征。
我们检查了一组与临床肿瘤相关的催乳素诱导肿瘤的特征：组织类型，ERα/孕激素受体（PR）表达和雌激素反应性，激活蛋白 1（AP-1）成分，信号转导和转录激活因子 5（Stat5）的磷酸化，细胞外信号调节激酶（ERK）1/2和 AKT。我们比较了女性中定义这种肿瘤亚型的 ERα 相关“腔隙”特征的“腔隙”特征中的转录本水平，以及各种乳腺上皮谱系中富集的转录本与其他经过充分研究的基因修饰的小鼠乳腺癌模型。最后，我们使用微阵列分析比较了催乳素诱导的 ERα+和 ERα-肿瘤，并在体内检查了对雌激素和抗雌激素 Faslodex 的反应性。
催乳素诱导的癌在组织类型，ERα/PR 表达和激活的信号级联方面具有显著的多样性。它们构成了一组异质但独特的小鼠乳腺肿瘤，具有人类乳腺癌腔隙亚型的分子特征。与 NRL-PRL 雌性中的形态正常和增生结构相反，癌对 ERα 介导的信号不敏感。这些肿瘤与鼠乳腺肿瘤病毒（MMTV）-neu 肿瘤不同，并且包含与腔隙/肺泡扩张和分化相关的因子的转录本升高，表明它们起源于催乳素的生理靶标。这些特征在 ERα+和 ERα-肿瘤中均存在，提示起源相同，尽管前者表现出反映更大分化的转录谱。
我们的研究表明，催乳素可以在小鼠中促进多种癌，其中许多类似于腔隙乳腺癌，为研究这种肿瘤亚型的发病机制，进展和治疗反应提供了一种新的实验模型。
