Elsevier

Life Sciences

Volume 239, 15 December 2019, 117009
Life Sciences

Review article
Heterogeneity of breast cancer: The importance of interaction between different tumor cell populations

https://doi.org/10.1016/j.lfs.2019.117009Get rights and content

Abstract

Introduction

Breast cancer is the most common cancer and the second leading cause of cancer-related death in women worldwide. Despite the early detection of breast cancer and increasing knowledge of its biology and chemo-resistance, metastatic breast cancer is largely incurable disease. We provide a review of the intertumor and intratumor heterogeneity, explain the differences between triple-negative breast cancer subtypes. Also, we describe the interaction of breast tumor cells with their microenvironment cells and explain how this interaction contributes to the tumor progression, metastasis formation and resistance to the treatment.

Discussion

One of the main causes that complicate the treatment is tumor heterogeneity. It is observed among patients (intertumor heterogeneity) and in each individual tumor (intratumor heterogeneity). In the case of intratumor heterogeneity, the tumor consists of different phenotypical cell populations. During breast cancer subtype identification, a small piece of solid tumor tissue does not necessarily represent all the tumor composition. Breast tumor cell phenotypical differences may appear due to cell localization in different tumor sites, unique response to the treatment, cell interaction with tumor microenvironment or tumor cell interaction with each other. This heterogeneity may lead to breast cancer aggressiveness and challenging treatment.

Conclusion

Understanding the molecular and cellular mechanisms of tumor heterogeneity that are relevant to the development of treatment resistance is a major area of research. Identification of differences between populations and their response to anticancer drugs would help to predict the potential resistance to chemotherapy and thus would help to select the most suitable anticancer treatment.

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.

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