Alkner Sara, Bendahl Pär-Ola, Ehinger Anna, Lövgren Kristina, Rydén Lisa, Fernö Mårten
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Medicon Village, SE-223 63, Lund, Sweden.
Skåne Clinic of Oncology, Skåne University Hospital Lund, SE-222 41, Lund, Sweden.
PLoS One. 2016 Mar 9;11(3):e0150977. doi: 10.1371/journal.pone.0150977. eCollection 2016.
The estrogen receptor coactivator Amplified in Breast Cancer 1 (AIB1) has been associated with an improved response to adjuvant tamoxifen in breast cancer, but also with endocrine treatment resistance. We hereby use metachronous contralateral breast cancer (CBC) developed despite prior adjuvant tamoxifen for the first tumor as an "in vivo"-model for tamoxifen resistance. AIB1-expression in the presumable resistant (CBC after prior tamoxifen) and naïve setting (CBC without prior tamoxifen) is compared and correlated to prognosis after CBC.
From a well-defined population-based cohort of CBC-patients we have constructed a unique tissue-microarray including >700 patients.
CBC developed after adjuvant tamoxifen more often had a HER2-positive/triple negative-subtype and a high AIB1-expression (37% vs. 23%, p = 0.009), than if no prior endocrine treatment had been administered. In patients with an estrogen receptor (ER) positive CBC, a high AIB1-expression correlated to an inferior prognosis. However, these patients seemed to respond to tamoxifen, but only if endocrine therapy had not been administered for BC1.
Metachronous CBC developed after prior endocrine treatment has a decreased ER-expression and an increased HER2-expression. This is consistent with endocrine treatment escape mechanisms previously suggested, and indicates metachronous CBC to be a putative model for studies of treatment resistance "in vivo". The increased AIB1-expression in CBC developed after prior tamoxifen suggests a role of AIB1 in endocrine treatment resistance. In addition, we found indications that the response to tamoxifen in CBC with a high AIB1-expression seem to differ depending on previous exposure to this drug. A different function for AIB1 in the tamoxifen treatment naïve vs. resistant setting is suggested, and may explain previously conflicting results where a high AIB1-expression has been correlated to both a good response to adjuvant tamoxifen and tamoxifen resistance.
雌激素受体共激活因子乳腺癌中扩增1（AIB1）与乳腺癌辅助性他莫昔芬治疗反应改善相关，但也与内分泌治疗耐药有关。我们在此将尽管先前对首个肿瘤进行了辅助性他莫昔芬治疗仍发生的异时性对侧乳腺癌（CBC）用作他莫昔芬耐药的“体内”模型。比较了可能耐药（先前接受他莫昔芬治疗后的CBC）和未接触过药物（未接受过他莫昔芬治疗的CBC）情况下的AIB1表达，并将其与CBC后的预后相关联。
从一个明确的基于人群的CBC患者队列中，我们构建了一个独特的组织微阵列，包含700多名患者。
与未进行过先前内分泌治疗的情况相比，辅助性他莫昔芬治疗后发生的CBC更常具有HER2阳性/三阴性亚型且AIB1表达较高（37%对23%，p = 0.009）。在雌激素受体（ER）阳性的CBC患者中，高AIB1表达与较差的预后相关。然而，这些患者似乎对他莫昔芬有反应，但前提是未对BC1进行过内分泌治疗。
先前内分泌治疗后发生的异时性CBC的ER表达降低，HER2表达增加。这与先前提出的内分泌治疗逃逸机制一致，并表明异时性CBC是“体内”治疗耐药性研究的一个假定模型。先前他莫昔芬治疗后发生的CBC中AIB1表达增加表明AIB1在内分泌治疗耐药中起作用。此外，我们发现有迹象表明，AIB1表达高的CBC对他莫昔芬的反应似乎因先前是否接触过该药物而有所不同。提示AIB1在未接触过他莫昔芬与耐药情况下具有不同功能，这可能解释了先前相互矛盾的结果，即高AIB1表达既与辅助性他莫昔芬治疗的良好反应相关，又与他莫昔芬耐药相关。
