Prolactin-Growth Factor Crosstalk Reduces Mammary Estrogen Responsiveness Despite Elevated ERα Expression
Prolactin-Growth Factor Crosstalk Reduces Mammary Estrogen Responsiveness Despite Elevated ERα Expression
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DOI：
10.2353/ajpath.2009.080719
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发表时间：
2009-03-01
影响因子：
6
通讯作者：
Schuler, Linda A.
中科院分区：
文献类型：
--
作者：
Arendt, Lisa M.;Grafwallner-Huseth, Tara L.;Schuler, Linda A.
大多数女性乳腺癌都表达雌激素受体 a (ER α)。然而，这些癌症中的很大一部分要么最初对抗雌激素治疗没有反应，要么对此类治疗方式产生耐药性。这种失败的一种假设机制是激素和局部生长因子之间的信号串扰。为了检查体内这些复杂的相互作用，我们评估了雌激素对转基因小鼠中转化生长因子 a (TCYF α) 和催乳素 (PRL) 诱导的乳腺肿瘤发生的影响。 PRL 和雌激素都减少了 TGF α 诱导的肿瘤发生的潜伏期，导致肿瘤呈不同程度的 ER α 阳性，但孕激素受体呈阴性。然而，尽管NRL-PRL/TGF α腺体中ER α水平升高，但肿瘤潜伏期并没有随着雌激素水平的增加而缩短，卵巢切除术后也没有增加。此外，与其他基因型相比，PRL 和 TGF α 组合可阻断雌激素的促有丝分裂作用，显着降低孕激素受体水平，并减少循环雌激素水平引起的 ERa 下调。然而，值得注意的是，导管形态仍然对雌激素有反应，表明 TGFα 和 PRL 组合可以抑制一些但不是全部雌激素信号。在体外和体内，PRL 和 TGF α 协同增强 Akt 磷酸化，而 Akt 磷酸化与人类疾病的内分泌抵抗相关。这些发现深入了解了乳腺肿瘤发生过程中 PRL 与生长因子的相互作用，并提出了可能提高治疗效果的组合方法。 （Am J Pathol 2009，174：1065-1074；DOI：10.2353/ajpath.2009.080719）
Most breast cancers that occur in women express estrogen receptor a (ER alpha). However, a large subset of these cancers either does not initially respond to antiestrogen therapy or develops resistance to such treatment modalities. one postulated mechanism of this failure is signaling cross talk between hormones and local growth factors. To examine these complex interactions in vivo, we assessed the effects of estrogen on transforming growth factor a (TCYF alpha)- and prolactin (PRL)-induced mammary tumorigenesis in transgenic mice. Both PRL and estrogen reduced the latency of TGF alpha-induced oncogenesis, resulting in tumors that were variably ER alpha-positive, but were progesterone receptor-negative. However, despite elevated ER alpha levels in NRL-PRL/TGF alpha glands, tumor latency was not reduced with Increasing estrogen levels, nor increased after ovarlectomy. Furthermore, PRL and TGF alpha in combination blocked the mitogenic effects of estrogen, dramatically reduced progesterone receptor levels, and diminished ERa down-regulation in response to circulating estrogen levels, in contrast to the other genotypes. Notably, however, ductal morphology remained responsive to estrogen, indicating that TGFa and PRL In combination can inhibit some, but not all, estrogenic signals. Both in vitro and in vivo, PRL and TGF alpha cooperatively enhanced Akt phosphorylation, which is associated with endocrine resistance in human disease. These findings provide insight into the Interactions of PRL with growth factors during mammary oncogenesis and suggest combinatorial approaches that may result in improved therapeutic efficacy. (Am J Pathol 2009, 174:1065-1074; DOI: 10.2353/ajpath.2009.080719)