Review articleHeterogeneity of breast cancer: The importance of interaction between different tumor cell populations
Graphical abstract
Introduction
Breast cancer is the most prevalent disease among women worldwide. Approximately 1.67 million new cases of this tumor were diagnosed in 2012 [1]. In 2018, new cases of breast cancer were diagnosed in nearly 2.1 million (11.6%) women, and about 627 thousand (6.6%) of women died from this type of cancer [2]. This prognosis suggests that several types of breast cancer are still incurable diseases leading to a high female mortality rate. Such aggressiveness of breast cancer may be due to the known heterogeneity of breast tumors [3]. One of the ways to determine cancer heterogeneity may be the identification of different cell phenotypes, cell density, or their localization in the tumor.
Heterogeneity typically exists between the similar type of tumors resulting in subtypes (intertumor heterogeneity), or within the tumors of the same type (intratumor heterogeneity). These specific subtypes are characterized by their molecular profiles, morphology, and expression of specific biomarkers (such as hormone estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 – HER2). For example, the part of cells that express the ER in breast tumors can alter widely, from 1 to 100% cells in the tumor [4].
Significant differences in individual tumors suggest that tumor cells can have various phenotypes with diverse functions and expression of different markers [4,5]. This intratumor heterogeneity is the tumor's ability to adapt to the new microenvironment conditions. Thus, tumor specimen taken during a biopsy does not necessarily represent the real tumor composition, because the tumor may consist of phenotypically different cancer cell populations with different properties and resistance to drugs. For this key reason, cancer treatment can be much more complicated [4].
Basal-like breast cancer subtype is considered to be one of the most aggressive ones and it is known as triple-negative breast cancer (TNBC) [6]. TNBC is characterized by reduced expression of hormone receptors. Currently, there is no molecular-based targeted therapy for TNBC. Therefore, TNBC is one of the highest priorities of current breast cancer research. More than 50% of patients diagnosed with TNBC at an early stage have a recurrence of the disease, and 37% of these patients die within the first 5 years, despite the treatment being applied [7]. The complicated treatment of TNBC can be associated with tumor heterogeneity. Nowadays, the TNBC classification into several different molecular TNBC subtypes is well known. Each molecular subtype has a different behavior of disease and response to treatment [8,9].
The variety of TNBC molecular subtypes proves the potential for heterogeneous tumors and may lead to further disease progression and treatment. The use of biological markers to identify subtypes of breast cancer has increased patient survival due to more accurate diagnosis of the disease. For example, when a breast cancer hormone receptor is detected, it is treated with endocrine therapy. HER2+ type tumors are usually treated with anti-HER2 therapy. Understanding breast cancer heterogeneity has become a significant achievement in identifying and treating breast cancer [10].
Therefore, it is very important to investigate breast cancer heterogeneity more thoroughly. Breast tumors can easily adapt to the unfavorable microenvironment, typically caused by standard chemotherapy or radiotherapy, remarkable lack of necessary oxygen, specific nutrients, etc. In this review, we focus on the interaction between phenotypically different cell populations and how it affects cancer development and resistance to chemotherapy.
Section snippets
Breast cancer heterogeneity
Intertumor heterogeneity typically describes key differences between tumors of the same origin in numerous patients (see Fig. 1a and b). These heterogeneous tumors have specific and individual molecular markers, unique biological behaviors and, as a result, different drug resistance and clinical outcomes [11]. Genetic mutations and/or epigenetic modifications are a source of intratumor heterogeneity. That explains why the same cell types have different phenotypic variants. Moreover, tumor
Clinical management of breast cancers based on intra- and/or intertumor heterogeneity
Knowledge and the clinical evaluation of breast tumor heterogeneity are of special importance in order to improve the patient treatment. The fast development of intertumor heterogeneity is not fit to the specific molecular classifications of breast tumors, which cause difficulties in clinical tumor identification and treatment [43]. The most complicated feature is intratumor heterogeneity as a temporal phenomenon different in each individual patient. This tumor “property” is closely related to
Triple-negative breast cancer heterogeneity
TNBC is a breast cancer subtype defined by a lack of expression of hormonal receptors ER, PR, and HER-2. Thus the treatment of this disease is complicated, and it is characterized by a very poor prognosis following progression [63]. Although the TNBC displays a positive response to chemotherapy (anthracyclines or/and taxanes-based), early and higher rates of distant metastases (e.g. lung, brain, bones) and recurrences are observed [64]. TNBC heterogeneity is the main barrier in conquering
Breast cancer phenotypic heterogeneity
Breast cancer classification based on immunohistochemical biomarkers is an important routine procedure to identify tumor subtype for the individual patient. However, sometimes breast cancer has features associated with different immunohistochemical phenotypes and it is impossible to assign it to specific breast cancer subtype. Breast cancer mixed phenotypes is a challenge to clinicians, especially when choosing the right targeting therapy [83].
Phenotypic heterogeneity became one of the most
Cell-cell interaction in breast cancer
Breast tumors are heterogeneous and consist of many different cell types. The heterogeneous population of stromal cells surrounds the tumor cells, and it creates tumor microenvironment (TME). Tumor development can influence its microenvironment and the microenvironment cells can affect tumor growth by secreted cytokines, growth factors, etc [91] (Fig. 4).
Nowadays researchers collect more and more evidences that TME is the key participant of tumor progression and response to the treatment. TME
Conclusions
Breast tumor is a heterogeneous disease and displays various sensitivities to chemotherapy. Breast cancer subtypes variety and different classification variants show tumors heterogeneity. One of the most aggressive breast cancer subtypes is TNBC that is divided into seven molecular subtypes with different disease progression and aggressiveness. In one breast tumor could exist different types of cancer cells populations and this heterogeneity complicate correct identification of disease subtype.
Funding
This research did not receive any additional funding.
Conflict of interest
The authors declare to have no conflict of interest.
Ethical approval
This article does not contain any interventional studies with human participants or animals performed by any of the authors.
References (109)
- et al.
Biological and therapeutic impact of intratumor heterogeneity in cancer evolution
Cancer Cell
(2015) - et al.
Her2-positive breast cancer: herceptin and beyond
Eur. J. Cancer
(2008) - et al.
Molecular heterogeneity in breast cancer: state of the science and implications for patient care
Semin. Cell Dev. Biol.
(2017) - et al.
Clonal evolution in breast cancer revealed by single nucleus genome sequencing
Nature
(2014) - et al.
Seminars in Cell & Developmental Biology Molecular heterogeneity in breast cancer : state of the science and implications for patient care
Semin. Cell Dev. Biol.
(2017) - et al.
Perspective biological and therapeutic impact of intratumor heterogeneity in cancer evolution
Cancer Cell
(2015) - et al.
Triple negative breast cancer: deciphering the biology and heterogeneity
Med. Univ.
(2016) - et al.
The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression
Mol. Oncol.
(2007) - et al.
Evaluating tumor heterogeneity in immunohistochemistry-stained breast cancer tissue
Lab. Investig.
(2012) - et al.
Accessories to the Crime : functions of cells recruited to the tumor microenvironment
Cancer Cell
(2012)
Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion
Cell
Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012
Int. J. Cancer
Global cancer statistics 2018 : GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
CA A Cancer J. Clin.
Survival study of triple-negative and non – triple- negative breast cancer in a Brazilian cohort
Clin. Med. Insights Oncol.
Cells of origin in cancer
Nature
The origins and implications of intratumor heterogenity
Cancer Prev. Res.
The molecular portraits of breast tumors are conserved across microarray platforms
BMC Genomics
Triple-Negative breast cancer: current practice and future directions
J. Oncol. Pract.
Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies
J. Clin. Investig.
Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer matthew
Clin. Cancer Res.
Phenotypic heterogeneity in modeling cancer evolution
PLoS One
Tumor stroma and regulation of cancer development
Annu. Rev. Pathol.
Heterogeneity in patient-derived tumour xenografts
Cancer Res.
Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases
J. Clin. Oncol.
Breast cancer intrinsic subtype classification, clinical use and future trends
Am. J. Cancer Res.
Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients
Breast Cancer Res.
Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype
Clin. Cancer Res.
Triple-Negative breast cancer: an unmet medical need
The Oncologist
Intrinsic subtypes and gene expression profiles in primary and metastatic breast cancer
Cancer Res.
Biological diversity in metastatic neoplasms: origins and implications
Science
Mouse models of cancers: opportunities to address heterogeneity of human cancer and evaluate therapeutic strategies
J. Mol. Med.
Intratumoral heterogeneity of immunohistochemical marker expression in breast carcinoma
Appl. Immunohistochem. Mol. Morphol.
Breast cancer intra-tumor heterogeneity
Breast Cancer Res.
Breast cancer intra-tumor heterogeneity: one tumor, different entities
Rev. Investig. Clin.
Triple negative breast cancer subtypes and pathologic complete response rate to neoadjuvant chemotherapy
Public Hist.
Clinical practice guidelines Primary breast cancer : ESMO Clinical Practice Guidelines for diagnosis , treatment and follow-up † clinical practice guidelines
Ann. Oncol.
ASCO-CAP guidelines for breast predictive factor Testing : an update
Appl. Immunohistochem. Mol. Morphol.
Recommendations for human epidermal growth factor receptor 2 testing in breast Cancer : American society of clinical oncology/college of American pathologists clinical practice guideline update
J. Clin. Oncol.
Tumour cell heterogeneity
F1000Research.
Comprehensive molecular portraits of human breast tumours
Nature
The implications of clonal genome evolution for cancer medicine
N. Engl. J. Med.
Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease
Nat. Rev. Clin. Oncol.
Understanding tumor ecosystems by single-cell sequencing : promises and limitations
Genome Biol.
Single-cell RNA-seq enables comprehensive tumour and immune cell profiling in primary breast cancer
Nat. Commun.
Inertial focusing for tumor antigen-dependent and -independent sorting of rare circulating tumor cells
Sci. Transl. Med.
Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition
Science
Single-cell identification in microbial communities by improved fluorescence in situ hybridization techniques
Nat. Rev. Microbiol.
Cytogenetic analysis
Scienc.
A pathology atlas of the human cancer transcriptome
Science
Cited by (130)
The rearrangement of co-cultured cellular model systems via collective cell migration
2023, Seminars in Cell and Developmental BiologyCrocin-loaded liposomes sensitize MDA-MB 231 breast cancer cells to doxorubicin by inducing apoptosis
2023, Process BiochemistryThe immune regulation and therapeutic potential of the SMAD gene family in breast cancer
2024, Scientific ReportsConditional generative adversarial network driven radiomic prediction of mutation status based on magnetic resonance imaging of breast cancer
2024, Journal of Translational MedicineAnalyses of hypoxia-related risk factors and clinical relevance in breast cancer
2024, Frontiers in Oncology