Breast cancer: origins and evolution

Abstract

Breast cancer is not a single disease, but rather is composed of distinct subtypes associated with different clinical outcomes. Understanding this heterogeneity is key for the development of targeted cancer-preventative and -therapeutic interventions. Current models explaining inter- and intratumoral diversity are the cancer stem cell and the clonal evolution hypotheses. Although tumor initiation and progression are predominantly driven by acquired genetic alterations, recent data implicate a role for microenvironmental and epigenetic changes as well. Comprehensive unbiased studies of tumors and patient populations have significantly advanced our molecular understanding of breast cancer, but translating these findings into clinical practice remains a challenge.

Figure 1. Hypothetical models explaining breast tumor subtypes.

Cell of origin (A) and tumor subtype–specific transforming event (B) models. Based on the cell of origin hypothesis, each tumor subtype is initiated in a different cell type (presumably stem or progenitor cell), whereas according to the model depicted in B, the cell of origin can be the same for different tumor subtypes and the tumor phenotype is primarily determined by acquired genetic and epigenetic events.

Figure 2. Hypothetical model of breast tumor progression.

Schematic view of normal, in situ, invasive, and metastatic carcinoma progression. Normal breast ducts are composed of the basement membrane and a layer of luminal epithelial and myoepithelial cells. Cells composing the stroma include various leukocytes, fibroblasts, myofibroblasts, and endothelial cells. In in situ carcinomas the myoepithelial cells are epigenetically and phenotypically altered and their number decreases, potentially due to degradation of the basement membrane. At the same time, the number of stromal fibroblasts, myofibroblasts, lymphocytes, and endothelial cells increases. Loss of myoepithelial cells and basement membrane results in invasive carcinomas, in which tumor cells can invade surrounding tissues and can migrate to distant organs, eventually leading to metastases.

Figure 3. Hypothetical model of human mammary epithelial stem cell hierarchy and differentiation.

(A) Hypothetical depiction of mammary epithelial stem cells and their various progeny. A bipotential stem cell gives rise to luminal epithelial and myoepithelial cells, but the intermediary steps and their regulation are largely unknown (question marks). The model is likely to oversimplify the real situation, since there are many different types of luminal epithelial cells and both the myoepithelial and luminal cells are likely different in the ducts and alveoli. (B) Schematic picture of a normal terminal duct lobular unit with the putative location of the various stem and differentiated cells indicated. Gray line denotes the basement membrane; color of cell types correlates with that in A. CK14, cytokeratin 14; MUC1, mucin 1.

Figure 4. Hypothetical models explaining intratumoral heterogeneity and tumor evolution.

(A) Based on the cancer stem cell hypothesis, differentiated cancer cells are progeny of cancer stem cells and they are not able to undergo self-renewing cell division. Thus, only the cancer stem cell can accumulate additional genetic changes that can drive tumor progression and drug resistance. (B) Based on the clonal evolution model, tumor cell phenotypes are determined based on the combination of cell type of origin of the tumor-initiating cell, acquired genetic and epigenetic alterations, and paracrine signals from surrounding cells. Cellular phenotypes are not stable and can change as the tumor evolves. All tumor cells have the capacity to undergo self-renewing division; thus they all have the potential to contribute to tumor progression and drug resistance. The two models do not have to be mutually exclusive, and their combination (e.g., clonal evolution of cancer stem cells) is also plausible.