Breast cancer (BC) is the cancer type with the highest incidence and mortality in women according to GLOBOCAN 2020 (Sung et al., 2021). The tumor heterogeneity of BC influences its tumorigenesis, from disease development to therapy response, with very important clinical implications (Nelson & Bissell, 2005). This necessitates a thorough exploration and comprehensive analysis of BC heterogeneity in order to improve the diagnosis, prognosis, and response to therapeutic modalties for BC.

Tumor heterogeneity refers to variations at genetic, epigenetic, transcriptomic, and proteomic profile levels within the tumor (intra-tumor heterogeneity), implicating the presence of genetically and phenotypically different cell subpopulations in the same tumor, among patients (intertumoral heterogeneity) or over the cancer progression or between the primary and secondary tumor (temporal heterogeneity). The intertumoral heterogeneity allowed the classification of BC determined by histology along with molecular phenotype in three broad groups: ER +/HER2− (luminal A), ER+/HER2 + (luminal B), and ER−/HER2− triple-negative breast cancer (TNBC) which does not express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) (https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf). Moreover, the tumor heterogeneity is affected regionally (spatial heterogeneity) by the tumor microenvironment (TME), including non-cancerous cells, for instance, cancer-associated fibroblasts (CAFs), immune cells, and vasculature, and the components of the extracellular matrix (ECM). Different architecture of the ECM components influences tissue geometry, cell behavior, and immune cell infiltration, all contributing to tumor heterogeneity. In addition, tumor heterogeneity is locally influenced by regional conditions, such as fibrosis, hypoxia, and nutrient availability. All these factors contribute to shaping cancer fate, from cancer development to therapy resistance and relapse (Nelson & Bissell, 2005).

Nowadays, the analysis of tumor heterogeneity, enabled by omics and digital pathology, allows the detection of multiple cancer cell populations and the identification of the phenotype, activation status, function, and distribution of immune, stromal, and endothelial cells within the tumor (Lee, Park, & Kim, 2021). A more accurate and deeper understanding of cancer heterogeneity will favor the improvement of diagnosis and therapeutic strategies leading to the development of personalized medicines that will benefit cancer patients.

As the mammary gland is an organ prone to undergo physiological and dynamic remodeling following the monthly reproductive hormonal cycle, during pregnancy, and lactation to perform its biological function during women’s lifespan, this heterogeneity is observed and translated in BC and represents a challenging obstacle for diagnosis and therapy.

In this mini review, we will strictly focus on the tumor-intrinsic and -extrinsic factors dictating the BC heterogeneity and we will discuss its implications in the therapeutic strategies with impact on the prognosis of BC patients.