Breast cancer is currently the leading cause of cancer death among women worldwide. AP-1 (c-Fos/c-Jun) is associated with proliferation and survival, while cytoplasmic c-Fos activates phospholipid synthesis in cells induced to differentiate or grow. Estrogen receptor α 46 (ERα46) is a splice variant of full-length ERα66 and it is known that it has an inhibitory role in cancer cell growth. We investigated c-Fos localization, its relationship to AP-1, the non genomic pathway of phospho-Tyr537-ERα66, as well as ERα46 and ERα66 isoforms in rat mammary gland development and carcinogenic transformation, and in mammary tumors. Female rats were injected: a) saline solution (Control mammary gland, CMG) or b) N-Nitroso-N-methyl urea (NMU), and samples were taken at 60, 90, 120 and 150 days of life. In addition, we analyzed hormone-dependent (HD) and independent (HI) tumors in ovariectomized rats, and intact tumors (IT) in non-ovariectomized ones. Our results show that, in CMG, nuclear c-Fos and proliferation decreased with age, AP-1 content was low, and nuclear ERα46/ERα66 ratio was higher than 1. In NMU, nuclear c-Fos and proliferation increased with carcinogenic transformation, AP-1 content was high, and nuclear ERα46/ERα66 was below 1. As tumor grade increased, proliferation, nuclear c-Fos and AP-1 expression were negatively associated to nuclear ERα46/ERα66 in IT. In HD, nuclear ERα46/ERα66, nuclear c-Fos expression, AP-1 levels and proliferation were lower than in HI, whose growth is estrogen-independent. Phospho-Tyr537-ERα66 content and ERK1/2 activation were associated with AP-1 levels and cell proliferation. Collectively, our findings support the notion that variant detection and ERα46/ERα66 ratio could shed light on the role of ERα isoforms in mammary gland transformation and the behavior of ERα positive mammary tumors.

中文翻译：

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雌激素受体α变体和c-Fos在大鼠乳腺和肿瘤中的表达。

乳腺癌目前是全世界女性癌症死亡的主要原因。AP-1（c-Fos / c-Jun）与增殖和存活有关，而细胞质c-Fos激活诱导分化或生长的细胞中的磷脂合成。雌激素受体α46（ERα46）是全长ERα66的剪接变体，众所周知，它对癌细胞的生长具有抑制作用。我们研究了c-Fos定位，其与AP-1的关系，磷酸Tyr537-ERα66的非基因组途径以及ERα46和ERα66亚型在大鼠乳腺发育和致癌性转化以及乳腺肿瘤中的作用。给雌性大鼠注射：a）盐溶液（对照乳腺，CMG）或b）N-亚硝基-N-甲基尿素（NMU），并在60、90、120和150天的生命中取样。此外，我们分析了去卵巢大鼠的激素依赖性（HD）和独立（HI）肿瘤，以及未去卵巢大鼠的完整肿瘤（IT）。我们的结果表明，在CMG中，核c-Fos和增殖随着年龄的增长而下降，AP-1含量低，并且核ERα46/ERα66的比率高于1。在NMU中，核c-Fos和增殖随着致癌性转化而增加， AP-1含量高，核ERα46/ERα66低于1。随着肿瘤级别的增加，IT中核ERα46/ERα66的增殖，核c-Fos和AP-1表达负相关。在HD中，核ERα46/ERα66，核c-Fos表达，AP-1水平和增殖低于HI，后者的生长与雌激素无关。磷酸-Tyr537-ERα66含量和ERK1 / 2活化与AP-1水平和细胞增殖有关。总的来说，