Background
Special AT-rich sequence binding protein 1 (SATB1) has been shown to regulate the expression of more than ten percent of genes by binding to the upstream regulatory regions which directly influence the promoter activity and gene expression [
1-
3]. SATB1 is reported to carry important weight to the progression of gastric cancer, cutaneous malignant melanoma, breast cancer, lung cancer, and lymphoma [
4,
5,
3,
6,
7]. A large number of target genes regulated by SATB1 involve in cancer cell proliferation, development and differentiation. Han et al. [
3] showed that SATB1 protein was detected in all 16 poorly differentiated infiltrating ductal breast carcinomas, and the human epidermal growth factor receptor 2 (HER2) gene was directly upregulated by SATB1.
HER2, also known as ERBB2, has been recognized as oncogenic protein with tyrosine kinase activity. Phosphorylation of HER2 could trigger downstream signaling events involved in malignant transformation and tumorigenesis, and ultimately result in poor clinical outcomes [
8,
9].
As a hormone-dependent tumor, ascertainment of estrogen-receptor (ER) and progesterone-receptor (PR) along with HER2 is regarded essential to treatment of breast cancer [
10,
11]. It is reported that positive expression of hormone-receptor (HR, including ER and/or PR) generally carries a better prognosis, on account of the target of response to endocrine therapy [
9,
11]. As a predictive marker, HER2 amplification values high in HER2 targeting therapy. In addition, the amplification of HER2 played a negative role in responding to endocrine sensitivity in recent discovery; over-expression of HER2 might lead to resistance to tamoxifen therapy [
12]. Thus, the interaction between HER2 and HR is probably directed by complex mechanisms.
In breast cancer progression, Ras/Raf/MEK/MAPK and PI3K/Akt/mTOR signaling pathways are commonly dysregulated by the crosstalk among various growth factors and hormone receptors including HER2 and ER [
13]. Several experimental studies demonstrate that the activation of these two signaling pathways by HER2 lead to phosphorylation and activation of ERα [
14]. Shigeaki Kato et al. [
14] reported that MAPKs could be activated through EGF-HER2 signaling pathway and the activated MAPK was able to phosphorylate the Ser 118 of ERα. PI3K signaling pathway, which is a major signaling hub downstream of HER2 and other receptor tyrosine kinases, could promote anti-estrogen resistance [
15]. Herein, HER2 can alter ER’s function and thereby contribute to tumor growth and tamoxifen resistance according to the signaling crosstalk between ER and HER2 pathways. Interestingly, Han et al. [
3] reported that MAPK signaling was activated and PI3K/mTOR signaling was suppressed by SATB1 in breast cancer cells. Therefore, the association among SATB1, HER2 and HR in breast cancer is still confounded.
Previous studies have demonstrated that HR expression correlated with low histological grade, while HER2 expression correlated with high histological grade in breast cancer [
10,
16]. It was reported that the expression of SATB1 was higher in poorly differentiated than in well differentiated breast cancer and completely absent in adjacent normal tissues [
3,
17]. But to our knowledge, little information has been available on the relationships among the expression of SATB1, HER2 and HR in breast cancer tissues so far.
The objectives of this study were to assess the correlations of SATB1 expression with HER2 and HR expression in breast cancer tissues, and to evaluate the effects of SATB1 expression on HER2 and HR expression as well as their relationships with clinicopathologic characteristics.
Discussion and conclusions
Human breast cancer is the most malignancy in women and is characterized by multitudinous genetic alterations [
24]. SATB1 is found acting as a “genome organizer” that functions as a landing platform to regulate tissue-specific gene expression [
25]. Aberrant expression of SATB1 in breast cancer cell lines can make rapid, major changes in gene expression pattern which could alter the cells’ cancerous phenotype [
3,
26]. Elimination of SATB1 in highly aggressive cancer cell lines alters a large number of gene expression and restrains tumor progress. On the contrary, breast cancer cell lines with ectopic expression of SATB1 experience great changes in their gene expression profile and develop a metastatic phenotype [
3]. Our study found that the expression of SATB1 was associated with higher histological grade in patients with breast cancer and SATB1 positive expression had a significantly lower survival rate than those with negative expression. The result was consistent to recent research reported by Heubner, whose work revealed a SATB1 haplotype demonstrating lower activity of SATB1 promotor, and this haplotype associated with improved prognosis [
27].
Among expression profile upregulated by SATB1, HER2 is an important regulator to breast cancer progression [
3,
19]. HER2, a proto-oncogene localized on chromosome 17, is amplified and/or the protein overexpressed in 15-25% of invasive breast cancer [
16]. HER2 amplification in breast cancer has been associated with increased invasiveness, tumourigenicity and worse clinical outcomes [
28]. What’s more, HER2, as a specific target, could predict the responsiveness to the monoclonal antibody treatment [
29]. Thus, HER2 amplification status has become an increasingly important and reliable predictor of patients’ treatment and outcome. In this study, we identified that SATB1 protein expression was associated with HER2 amplification in breast cancer tissues. As has been confirmed, SATB1 could directly upregulate HER2 amplification. Through a series of successive regulation of SATB1 and HER2, the breast cancer performed more malignant activities. However, we also found samples with SATB1-/HER2+ and SATB1+/HER2- expression patterns. This phenomenon reflected that HER2 was not always modulated by SATB1. Some other regulated factors also functioned, such as Chromosome17 polysomy [
23,
30].
The hormone receptors play an important role in the pathogenesis in breast cancer. By binding with estrogen-responsive elements in the genome, they recruit a series of cofactors that facilitate gene transcription [
31]. Consequently, they were regarded as effective target to endocrine therapy. However, recent retrospective studies have suggested that HER2+ tumors may be less sensitive to endocrine treatments [
28,
32]. In our study, a clear and strong negative association between HER2 and HR in breast cancer was observed. Namely, HR usually negative expressed while HER2 overexpressed in breast cancer, which was in keep with previous studies [
10,
16]. The inverse association between HER2 and HR levels in clinical specimens is in sympathy with cell line data in a prior study by Pietras [
33]. In their study, they introduced HER2 cDNA into MCF7 (which is HER2 low and ER positive cell line) and discovered the transcripts and protein suppression of ER in the transfected cells [
33]. This might explain the phenomenon that HER2 amplification/overexpression is consistent with negative HR status. Not only decreasing ER expression, HER2 usually induces the failure of endocrine treatment, such as tamoxifen therapy. In our study, a significantly negative association between SATB1 and HR was also found. Furthermore, the inverse relevance was observed between the co-expression of SATB1/HER2 and HR expression in breast cancer patients. HER2 could regulate ER expression and play a role in the resistance to hormonal, chemo- and radiotherapy [
32]. Kobierzycki et al. found a moderate positive correlation between Ki-67 and SATB1 expression and the correlation was even obvious in ER-negative patients (r = 0.291, p = 0.045 independently on the receptor status, and r = 0.392, p = 0.032 in ER-negative tumors) [
34], which indicates an indirect role of SATB1 in the cancer cell proliferation. SATB1 could upregulate gene expressions which are associated with tumor cell resistance to apoptosis and multidrug treatment, such as BCL2 and MDR [
1,
19]. In vitro studies have demonstrated that elevated expression of SATB1 contributes to maintenance of the malignant phenotype and resistance to chemotherapeutic drugs in many other cancers [
35,
36]. Collectively, SATB1 might inhibit HR expression in cooperate with HER2 and promotes tumor progression or estrogen therapy resistance in breast cancer.
Previous data indicated that HER2 was amplified more commonly in higher histological grade than lower grade in breast cancer [
8,
16,
18]. Similar to these studies, our results showed that HER2 was associated with advanced histological grade in breast cancer. Han et al. [
3] reported that SATB1 expression was significantly higher in poorly differentiated tissues. Patani et al. [
2] detected SATB1 mRNA increased in high histological grade breast cancer. Accordingly, we also found there was significant correlation between SATB1 and breast cancer histological grade. Moreover, co-expression of SATB1 and HER2 was significantly associated with advanced tumor histological grade in breast cancer patients. Histological grade was an important index of poor differentiation in breast cancer. Our results suggested that HER2+, SATB1+ and SATB1/HER2 co-expression associated with high degree of malignancy in breast cancer. They may play an important role to promote cancer cell proliferation and differentiation. However, no association was observed between HR expression and tumor histological grade. Kaplan–Meier survival analyses demonstrated that SATB1/HER2 single positive and co-expression patients inclined to have poor prognosis, whereas HR positive expression tended to get preferable outcome. Cox regression analyses elucidated that SATB1 and HER2 were independent risk factors for patients’ survival in breast cancer and HR was a protective factor.
Based on the results above, the expression of HER2 had synergistic effect with SATB1 in breast cancer and HR had reverse influence compared to SATB1 and HER2. There might be intrinsic linkage among SATB1, HER2 and HR. Further researches are needed to expound the elaborate mechanism of the crosstalk and regulatory network among SATB1, HER2 and HR.
In conclusion, this study has reported on the relationships between SATB1, HER2, HR expression and clinicopathologic characteristics in breast cancer tissues. SATB1+, HER2+ and SATB1/HER2 co-expression correlated with higher histological grade and were independent risk factors of patients’ survival, which suggested that SATB1/HER2 positive expression weighed highly with poorly differentiated breast cancer and HR were protective factors. Further researches of therapeutics targeting the inner link or crosstalk among SATB1, HER2 and HR would give maximum benefits to patients with breast cancer.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
XL, YZ, JW and CQ did the immunohistochemical analysis. FQ and BD reviewed all the pathological slides. XL, YZ, JW analyzed the data. YW designed the study. YS drafted the manuscript. All authors read and approved the final manuscript.