Identifying DEGs in breast cancer based on multiomics data
For mRNA, DNA methylation, copy number variation, and somatic mutation, we identified 2,388, 1,442, 3,348, and 8,543 DEGs, respectively. Among them, there were 1,020 highly expressed genes, 1,368 low-expressed genes, 670 significantly hypermethylated genes, 770 significantly hypomethylated genes, 715 copies of copy-numbered genes, and 2,633 copies of deleted genes. The numbers of upregulated DEGs with DNA methylation, DNA copy number, and somatic mutations consistent with mRNA expression were 35, 30, and 138, respectively; the number of downregulated DEGs was 76, 89, and 359, respectively (Fig. 2).
Identifying significantly enriched biological pathways and functions based on DEGs
We performed pathway enrichment analysis of methylation, copy number, and mutant disease risk genes, and took the significantly enriched pathway TOP20 as an example (Fig. 3A). The results showed that DNA methylation, copy number, and mutation-driven breast cancer risk genes were significantly enriched in “pathways in cancer,” “microRNAs (miRNAs) in cancer,” “PI3K-Akt signaling pathway,” and “cell adhesion molecules (CAMs).” PI3K-Akt is a signaling pathway for a variety of cancers that regulates many basic cellular functions such as DNA transcription, protein translation, cell proliferation, cell growth, and survival . It also controls key cellular processes of cancer through phosphorylation. CAM is a glycoprotein that plays a key role in a variety of biological processes [20, 21]. Existing studies have shown that expression of CAM is associated with cancer [22–24]. We performed functional enrichment analysis on methylation, copy number, and mutant disease risk genes. The results showed that DNA methylation, copy number, and mutation-driven breast cancer risk genes were significantly enriched in the “negative regulation of apoptotic process” and “positive regulation of cell proliferation/negative regulation of cell proliferation.” Apoptosis is widely recognized as a positive process for the prevention and treatment of cancer, but apoptosis may also lead to adverse reactions and may even promote cancer. It has been found that many non-coding RNAs regulate apoptosis and play a positive role in tumor cell therapy. Cell proliferation is one of the most important life characteristics of humans. Tumor cells proliferate more rapidly and increase in number geometrically compared to normal cells. It also destroys the life cycle and division cycle of normal cells and acquires the ability to prolong proliferation and growth, which is one of the difficulties in treating cancer [25, 26].
Methylation-driven Drug Gene Association Network
We used the DD Score method to re-target methylated human FLNs to obtain a methylation-driven drug gene association network. Literature mining for breast cancer resetting drug targets and resetting drugs in the network showed that a large number of studies have reported that breast cancer reset drug targets are closely related to cancer, and may serve as novel drugs for breast cancer treatment. For example, López-Ozuna et al.found that the mRNA and protein expression of the prolactin receptor (PRLR) is downregulated in triple-negative breast cancer (TNBC). At the same time, PRLR gene expression has been used to subclassify TNBC patients into a new subgroup (TNBC-PRLR) characterized by epithelial luminal differentiation. The restoration/activation of the PRL pathway in TNBC cells representative of mesenchymal or TNBC-PRLR subgroups led to induction of the epithelial phenotype and suppression of tumorigenesis. These results offer potential new modalities for TNBC stratification and development of personalized therapy based on PRL pathway activation. Kelly  found that PRLR is expressed in breast cancer and promotes cancer. Urban studies  have found that the mRNA and protein expression of glycoprotein M6B (GPM6B) is associated with various types of gynecologic malignancies. N-myc downstream regulatory gene 2 (NDRG2), a well-known tumor suppressor, was identified as a potential target gene for miR-454, and miR-454 directly targets the 3'-untranslated region of NDRG2. Gao  found that miR-454 is a key regulator of tumorigenesis, and can act as an oncogene or a tumor suppressor. At the same time, they found that miR-454 overexpression significantly inhibited NDRG2 expression, and small interfering RNA (siRNA)-mediated NDRG2 significantly reversed the anti-tumor effect of miR-454 inhibition on cancer cell proliferation and invasion. Kim  found that inhibition of NF-κB signaling by NDRG2 gene expression downregulated cyclooxygenase-2 expression, thereby inhibiting the migration and invasion of breast cancer cells (Fig. 4A).
Copy Number-driven Drug Gene Association Network
We used the DD Score method to re-target the copy number human FLNs to obtain a copy number-driven drug gene association network. For example, Yen  found that expression of acyl-CoA synthetase long chain family member 1 (ACSL1) in the estrogen receptor (ER)-negative group was higher than that in the ER-positive group, and high ACSL5 expression was associated with good prognosis in patients with both ER-positive and ER-negative breast cancer. These results suggest that ACSL1 expression is regulated by ER signaling pathways, and may be a potential novel biomarker for predicting the prognosis of breast cancer patients. Wang  found that ACSL1 mRNA expression levels were significantly upregulated in clinical breast cancer tissues, and oncoprotein Hepatitis B virus X-interacting protein upregulated ACSL1 in breast cancer by activating transcription factor Sp1. The Aikins study  found that transgelin is an actin-binding protein associated with multiple stages of cancer development, such as proliferation, migration, and invasion. The authors studied the role of transgelin in vasculogenic mimicry (VM) and evaluated the effects of VM on endothelial cell- and angiogenesis related-gene expression in MDA-MB-231 breast cancer cells. The results suggested that downregulation of transgelin (TAGLN) inhibits interleukin-8, thereby inhibiting VM in breast cancer cells, and through this mechanism, TAGLN and VM together inhibit malignant tumors. Many studies have shown that the high expression of Kinesin Family Member 26B (KIF26B) is directly related to a poor prognosis in breast cancer. Teng’s study found a significant increase in KIF26B levels in breast cancer cells and patient samples, and KIF26B levels correlated with tumor size, TNM grade, and degree of differentiation in breast cancer patients. Overexpression of KIF26B promotes breast cancer cell proliferation and migration by activating FGF2/ERK signaling, whereas silencing KIF26B has the opposite effect. Experimental studies have shown that KIF26B promotes the development and progression of breast cancer and may become a potential therapeutic target for the treatment of breast cancer. Non-receptor tyrosine kinases, such as protein tyrosine kinase 6 (PTK6), are highly expressed in a variety of tumor types, including prostate, ovarian, and breast cancers, and modulate oncogenic phenotypes such as proliferation, migration, and survival. PTK6 inhibition also overcomes targeted therapy resistance of human epidermal growth factor 2-positive breast cancer. Although PTK6 is highly expressed in ER + Luminal breast cancers, the role of PTK6 in this subtype has not been elucidated. The Park study  elucidated the critical functions of PTK6 in ER + Luminal breast cancers and support PTK6 as an attractive therapeutic target for ER + breast cancer (Fig. 4B).
Mutation-driven Drug Gene Association Network
We used the DD Score method to re-target the mutation human FLNs to obtain a mutation-driven drug gene association network. For example, Litviakov's experimental study  indicated that the absence of ABCC5 predicted a good response to neoadjuvant chemotherapy in breast cancer. Li’s experimental study  found that high Minichromosome Maintenance 10 Replication Initiation Factor (MCM10) immune expression was significantly associated with the presence of advanced primary tumors, lymph node status, and vascular invasion in cancer. Low expression of MCM10 gene significantly inhibited cell proliferation in J82 and TCCSUP human bladder carcinoma cells. The experimental results indicated that MCM10 overexpression was associated with poor clinical pathological features and independent negative prognosis, which have potential therapeutic diagnostic value in cancer. Fu  found that solute carrier family 22 member 3 (SLC22A3) is a metastasis suppressor in esophageal squamous cell carcinoma (ESCC), which is significantly downregulated in non-tumor esophageal tissues of patients with familial ESCC and is significantly associated with lymph node metastasis. A-to-I RNA editing of the SLC22A3 gene results in reduced expression in non-tumor esophageal tissues of familial ESCC. Their study showed that A-to-I RNA editing of SLC22A3 contributed to the early development and progression of familial esophageal cancer in high-risk individuals (Fig. 4C).
Multiomics Joint-driven Drug Gene Association Network
We used the DD Score method to retarget the multi-omics human functional linkages network to obtain a multi-omics joint-driven drug gene association network. For example, placental-specific protein 1 (Plac1) is a cancer antigen that plays a key role in promoting the initiation and progression of cancer. Feng  study found that Plac1 expression was positively correlated with clinical stage, lymph node metastasis, hormone receptor status, and overall patient survival. Overexpression of Plac1 promoted invasion and metastasis of breast cancer cells in vitro and in vivo. The experimental results indicate that the functional interaction between Plac1 and furin enhances the invasion and metastasis of breast cancer, and the furin/NICD/PTEN axis may be an important therapeutic target for breast cancer treatment. Yang  study found that Plac1 is a cancer-associated protein that is upregulated in a variety of malignant tissues including prostate cancer, gastric adenocarcinoma, colorectal cancer, epithelial ovarian cancer, and breast cancer. It is significantly upregulated in cancer tissues, and its expression level is associated with advanced pathological stage and shorter progression-free survival of cancer patients. Furthermore, downregulation of Plac1 expression by siRNA inhibited cell proliferation, induced apoptosis, and disrupted the invasive ability of cancer cells. These results suggest that upregulated Plac1 can be used as a negative prognostic biomarker in cancer and regulate cell proliferation and invasion. Eriksson  found that breast size-related gene (COMTD1) mutations affect breast cancer risk. FAM107A (TU3A), located at 3p21.1, was identified as a candidate tumor suppressor gene in renal cell carcinoma. Awakura  found that TU3A promoter hypermethylation was observed in several types of cancer cell lines and primary cancers of the bladder and testis. These results demonstrated for the first time the epigenetic inactivation of TU3A in human cancers and have important implications for studying the role of TU3A methylation in cancer development. Also known as Gravin and SSeCKS, AKAP12 is a novel potent scaffolding protein for many key signaling factors, such as protein kinase C (PKC), PKA, cyclin and F-actin. AKAP12 expression is inhibited in a variety of malignancies including breast cancer, prostate cancer, gastric cancer, and colon cancer. Soh  found that AKAP12 is a potential breast cancer metastasis suppressor. Zhang  found that the non-methylation of AOX1 is a risk factor for breast cancer.
Prognostic Utility Of Reset Drug Targets In Breast Cancer
The DD Score method was used to reset drug targets for breast cancer, and the survival and survminer R packages were used to perform survival analysis. The targets significantly classified high-risk and low-risk groups of breast cancer patients with strong prognostic efficacy. The methylation-driven gene GPM6B has a P value of 0.00141, a copy number driven gene ACSL1, a P value of 0.0582, a mutation-driven gene MCM10, a P value of 0.0303, and a multiomics joint-driven drug gene COMTD1 with a P value of 0.0071. A significantly high expression of GPM6B, a methylation-driven breast cancer replacement drug target, was significantly associated with a better prognosis. Urban studies have shown that increased mRNA and protein expression of Gpm6B is associated with various types of gynecologic malignancies. At the same time, its targeted drug methotrexate is an anti-tumor drug with immunosuppressive properties, which can be used alone or in combination with other anticancer agents for the treatment of breast cancer. Significant low expression of ACSL1 is markedly associated with a better prognosis in copy-driven breast cancer replacement drug targets. Yen found that ACSL1 expression is regulated by the ER signaling pathway and is a potential novel biomarker for predicting the prognosis of breast cancer patients. At the same time, its targeted drug mitomycin is an anti-tumor antibiotic produced by Streptomyces caespitosus for the treatment of malignant tumors of the lips, mouth, pharynx, digestive organs, peritoneum, female breasts and bladder. Significantly low expression of MCM10, a mutation-driven breast cancer replacement drug target, is significantly associated with better prognosis. Li found that high MCM10 immune expression is significantly associated with the presence of advanced primary tumors, lymph node status, and vascular invasion in cancer. Low gene expression of MCM10 significantly inhibited cell proliferation in J82 and TCCSUP cells. Its targeted drugs including Mitomycin, Methotrexate and Estradiol. Estradiol is a naturally occurring hormone that can be used to treat breast cancer (for relief only). Significantly low expression of the breast cancer replacement drug target COMTD1, a multiomics combination-driven drug gene network, was significantly associated with better prognosis. The Eriksson N study found that breast size-related gene (COMTD1) mutations affect breast cancer risk. Its targeted drug, cisplatin, is a platinum-based chemotherapy drug used to treat various types of cancer, including sarcoma, small cell lung cancer, ovarian cancer, lymphoma, and germ cell tumors.