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Matou-Nasri, S.; Aldawood, M.; Alanazi, F.; Khan, A.L. Epidemiology—TNBC Risk in T2DM Patients. Encyclopedia. Available online: (accessed on 28 November 2023).
Matou-Nasri S, Aldawood M, Alanazi F, Khan AL. Epidemiology—TNBC Risk in T2DM Patients. Encyclopedia. Available at: Accessed November 28, 2023.
Matou-Nasri, Sabine, Maram Aldawood, Fatimah Alanazi, Abdul Latif Khan. "Epidemiology—TNBC Risk in T2DM Patients" Encyclopedia, (accessed November 28, 2023).
Matou-Nasri, S., Aldawood, M., Alanazi, F., & Khan, A.L.(2023, July 25). Epidemiology—TNBC Risk in T2DM Patients. In Encyclopedia.
Matou-Nasri, Sabine, et al. "Epidemiology—TNBC Risk in T2DM Patients." Encyclopedia. Web. 25 July, 2023.
Epidemiology—TNBC Risk in T2DM Patients

Triple-negative breast cancer (TNBC) is usually the most malignant and aggressive mammary epithelial tumor characterized by the lack of expression for estrogen receptors and progesterone receptors, and the absence of epidermal growth factor receptor (HER)2 amplification. Corresponding to 15–20% of all breast cancers and well-known by its poor clinical outcome, this negative receptor expression deprives TNBC from targeted therapy and makes its management therapeutically challenging. Type 2 diabetes mellitus (T2DM) is the most common ageing metabolic disorder due to insulin deficiency or resistance resulting in hyperglycemia, hyperinsulinemia, and hyperlipidemia. Due to metabolic and hormonal imbalances, there are many interplays between both chronic disorders leading to increased risk of breast cancer, especially TNBC, diagnosed in T2DM patients.

triple-negative breast cancer type 2 diabetes mellitus risk factors

1. TNBC, the Major Breast Cancer Subtype in T2DM Patients

Patients with T2DM have an increased risk of developing TNBC, a heterogeneous group of breast carcinomas with most of them characterized by a fast-growing and aggressive subtype with different genetic profiles. Some rare TNBC cases are low-grade and poorly invasive with an indolent clinical outcome; however, TNBC is frequently diagnosed at a later stage, associated with a larger tumor size, a higher tumor grade, poorly differentiated invasive ductal carcinoma histological subtype, increased rate of lymph metastasis, and associated with a poor 5-year survival [1][2]. TNBC is often characterized by early systemic relapse. High proliferative breast cancers such as TNBC are more likely to be missed in regular screening [3]. Early detection of TNBC is crucial as TNBC rapidly grows and spreads, although responding well to neoadjuvant chemotherapy, few TNBCs that respond less reoccur sooner. In addition, invasive TNBCs present high potential for metastases, particularly in the lungs and the brain. TNBC is also a rapidly evolving disease, associated with young age, and shows benign features, including an oval or round shape, a smooth or circumscribed margin, and is less likely to have an echogenic halo as a sign of malignancy [4].

2. TNBC Subtypes

TNBC, a highly invasive heterogeneous subtype with the poorest outcome, is clinically and molecularly defined by the lack of estrogen receptor (ER-negative or ER) and progesterone receptor (PR-negative or PR) expression and the absence of human epidermal growth factor receptor 2 (HER2-negative, HER2) overexpression detected by immunohistochemistry (IHC) staining. However, recently, a negligible percentage corresponding to less than 1% of ER and PR expression has been detected [5]. Among all the breast cancer cases, one woman out five or even six develops TNBC [6]. Using magnetic resonance imaging in 1090 women (mean of 52.1 years) of whom 256 were diagnosed with TNBC and 846 were diagnosed with ER-positive, the TNBC was revealed to be closer to the chest with a tendency to develop towards a posterior or prepectoral location compared with the ER-positive breast cancers [7]. An in-depth knowledge of the TNBC at the molecular level enables the establishment of rational stratification reflecting intrinsic and clinical differences between subtypes in response to various therapies to sharpen the treatment approaches for better clinical outcomes [6][8][9][10]. Thus, the clinical relevance of the TNBC subtype classification has been correlated with chemotherapeutic response and eventually to the prediction of the tumor pathologic complete response (pCR) [11][12]. Based on transcriptome expression profile analysis of invasive carcinomas and their drug sensitivity, Lehmann and colleagues established the classification of TNBC into seven distinct clusters also named as subtypes, including one uncharacterizable unstable (UNS) subtype and six well-characterized stable subtypes [13]. The transcriptional analysis of the stable subtypes revealed two basal-like (BL1 and BL2) subtypes harboring proliferation genes, an immune-modulatory (IM) subtype enriched with immune-associated genes, a mesenchymal (M) subtype characterized by cell motility, a mesenchymal stem-like (MSL) subtype highly expressing angiogenesis- and stemness-related genes, and a luminal-androgen receptor (LAR) subtype sensitive to androgen activity and enriched in HER2 expression (Table 1). Considering extrinsic signals emitted from immune and stromal cells, Brown’s group (2015) classified 198 breast tumors into only four TNBC subtypes, which are BL-immunosuppressed, BL-immunoactivated, MSL, and LAR based on genomic analysis [14]. Lehmann and colleagues also refined the TNBC classification to TNBCtype-4 (BL1, BL2, M, and LAR) based on lymphocyte infiltration, stromal mesenchymal cell gene expression, and the response to neoadjuvant chemotherapy [15]. At the diagnosis, the BL (expressing marker of the myoepithelium of the normal gland) is revealed as the major TNBC subtype, representing 80% of all subtypes while 15% of TNBCs are the LAR subtype [16].

3. Genetic Mutations in TNBC Subtypes

The main genetic mutations, reported to be strongly associated with TNBC development, are breast cancer genes. Both BRCA1/2 mutations are majorly detected in BL1 while the BRCA1 mutation is also detected in the BL1 and MSL TNBC subtypes [17]. The tumor suppressor TP53, phosphatase and tensin homolog (PTEN), and cyclin-dependent kinase inhibitor 2A (CDKN2A) gene mutations are often found in BL1, BL2, and ML subtypes while the LAR TNBC subtype harbors TP53, PTEN, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene mutations. Considering TNBC clinical behavior, prognosis, and multidrug resistance, a PTEN-reduced/PI3K-high/mammalian target of rapamycin (mTOR)-high expression is suggested to constitute a high-risk profile of TNBC progression [18]. The metastatic MSL TNBC subtype is mainly characterized by mutations in angiogenesis-related genes such as HRAS, KRAS, and platelet-derived growth factor receptor-alpha (PDGFRA). The two other TNBC subtypes contain genomic alterations resulting in mutations in immune-related genes such as nuclear factor kappa-B inhibitor alpha (NFKBIA) and tumor suppressor APC [19]. Added to the characterization of the TNBC subtypes, the related signaling pathways, genetic markers, and potential therapy are summarized in the Table 1.

4. Risk Factors

Although the specific etiology of TNBC has not been described, many predisposing risk factors such as gender; age; genetic mutations and family history; reproductive history; ethnicity; and precipitating risk factors, including body mass index (BMI), physical inactivity, sex hormonal imbalances, vitamin supplements, alcohol intake and smoking, and metabolic syndrome, have led to TNBC occurrence [20]. While T2DM is an independent risk factor of TNBC, the main T2DM-related risk factors associated with TNBC onset and development are age, high BMI (i.e., overweight and obesity), and physical inactivity.
Table 1. Characterization of triple-negative breast cancer subtypes according to Lehmann classification.


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