Deletions of multidrug resistance gene loci in breast cancer leads to the down-regulation of its expression and predict tumor response to neoadjuvant chemotherapy

Abstract

Neoadjuvant chemotherapy (NAC) is intensively used for the treatment of primary breast cancer. In our previous studies, we reported that clinical tumor response to NAC is associated with the change of multidrug resistance (MDR) gene expression in tumors after chemotherapy. In this study we performed a combined analysis of MDR gene locus deletions in tumor DNA, MDR gene expression and clinical response to NAC in 73 BC patients. Copy number variations (CNVs) in biopsy specimens were tested using high-density microarray platform CytoScanTM HD Array (Affymetrix, USA). 75%–100% persons having deletions of MDR gene loci demonstrated the down-regulation of MDR gene expression. Expression of MDR genes was 2–8 times lower in patients with deletion than in patients having no deletion only in post-NAC tumors samples but not in tumor tissue before chemotherapy. All patients with deletions of ABCB1 ABCB 3 ABCC5 gene loci – 7q21.1, 6p21.32, 3q27 correspondingly, and most patients having deletions in ABCC1 (16p13.1), ABCC2 (10q24), ABCG1 (21q22.3), ABCG2 (4q22.1), responded favorably to NAC. The analysis of all CNVs, including both amplification and deletion showed that the frequency of 13q14.2 deletion was 85% among patients bearing tumor with the deletion at least in one MDR gene locus versus 9% in patients with no deletions. Differences in the frequency of 13q14.2 deletions between the two groups were statistically significant (p = 2.03 ×10−11, Fisher test, Bonferroni-adjusted p = 1.73 × 10−8). In conclusion, our study for the first time demonstrates that deletion MDR gene loci can be used as predictive marker for tumor response to NAC.

The molecular basis of breast cancer pathological phenotypes

“…Downregulated genes and pathways with marked apocrine features were those encoding gastropeptides ( NPYIR and PI16 ) and serine peptidase ( KLK11 ), and those involved in alcohol/drug metabolism ( ADH1B and CYP4F22 ), secretion ( AQP5 ), the extracellular matrix ( HAPLN1 ), and cytokine signalling ( C7 and DARC ). These genes have been investigated as markers of proliferation or metastasis , breast cancer risk , prognosis , and response to therapy . Our work suggests that drug resistance may occur in tumours with marked apocrine features with overexpression of ATP‐binding cassette transporter mRNA, and new drugs targeting aquaporin water channels may not work in these tumours .…”

Intratumoral Morphological Heterogeneity of Breast Cancer As an Indicator of the Metastatic Potential and Tumor Chemosensitivity

“…Chemotherapy-induced changes in tumor cells largely determine the further course of the disease: drug resistance, metastasis, and recurrence [23-25]. In this regard, we analyzed two independent samples of BC patients with and without NAC treatment.…”

“…There is ample evidence that preoperative chemotherapy is able to modify the genome of tumor cells and affect the tumor population structure [23-25]. The molecular profile of primary tumor samples of triple-negative BC after NAC was shown to differ from the profile of biopsy samples of the same tumors before chemotherapy [34].…”

A 3q gene signature associated with triple negative breast cancer organ specific metastasis and response to neoadjuvant chemotherapy

“…Moreover, none of our 3q 19 genes overlaps with known gene signatures tested in this study, arguing a lack of efficacy of using these known gene signatures as prognostic factors in TNBC patients. Although the exact role of these 19 genes in breast cancer metastasis is unclear, 12 genes including FXR1 have been studied functionally or mechanistically in human cancers including lung and breast (Supplemental Table 21)919202122232425. For instance, PIK3CA is the most well-studied oncogene among our 3q gene signature due to its high mutation rate in human cancer, especially in breast cancer23.…”