Microenvironmental influences that drive progression from benign breast disease to invasive breast cancer

Abstract

Invasive breast cancer represents the endpoint of a developmental process that originates in the terminal duct lobular units and is believed to progress through stages of increasing proliferation, atypical hyperplasia, and carcinoma in situ before the cancer acquires invasive and metastatic capabilities. By comparison with invasive breast cancer, which has been studied extensively, the preceding stages of benign breast disease are more poorly understood. Much less is known about the molecular changes underlying benign breast disease development and progression, as well as the transition from in situ into invasive disease. Even less focus has been given to the specific role of stroma in this progression. The reasons for lack of knowledge about these lesions often come from their small size and limited sample availability. More challenges are posed by limitations of the models used to investigate the lesions preceding invasive breast cancer. However, recent studies have identified alterations in stromal cell function that may be critical for disease progression from benign disease to invasive cancer: key functions of myoepithelial cells that maintain tissue structure are lost, while tissue fibroblasts become activated to produce proteases that degrade the extracellular matrix and trigger the invasive cellular phenotype. Gene expression profiling of stromal alterations associated with disease progression has also identified key transcriptional changes that occur early in disease development. In this review, we will summarize recent studies showing how stromal factors can facilitate progression of ductal carcinoma in situ to invasive disease. We also suggest approaches to identify processes that control earlier stages of disease progression.

Figure 1

Pathological characteristics associated with breast cancer progression. a Normal terminal duct lobular unit (TDLU), the anatomic substructure from which breast cancer originates, containing numerous individual acini and surrounded by interlobular stroma. b Model of progression from normal epithelium through benign breast disease to invasive breast cancer, indicating relative lifetime risk for cancer development as compared to women with no proliferative disease. Women with proliferative disease without atypia (PDWA) have an increased relative risk (RR) of 1.3–1.9; women with atypical hyperplasia (atypia) have RR of 3.5–5.3; women with ductal carcinoma in situ (DCIS) have RR of 10–11. c Stages of progression from benign breast disease to invasive, metastatic breast cancer. a Nonproliferative disease depicting mammary cysts, fluid-filled structures derived from TDLU. b Proliferative disease without atypia (PDWA): adenosis, a proliferative lesion characterized by increased number or size of glandular structures. c PDWA: moderate hyperplasia, characterized by an increased number of epithelial cells in breast ducts and lobules with 5 or more cells above the basement membrane, often with bridging of the luminal space. d PDWA: florid hyperplasia, in which hyperplastic cells with unevenly distributed nuclei proliferate in solid clusters distending the lumens and often leading to their complete closing and loss e Atypical ductal hyperplasia, epithelial hyperplasia with bridging architecture and monotonous cytologic features suggesting expansion of a cell population. f Atypical lobular hyperplasia characterized by enlarged lobules partially involved with acini expanded with monotonous dyshesive epithelial cells. g Ductal carcinoma in situ, a malignant proliferation of epithelial cells remaining within the basement membrane; some surrounding inflammatory infiltrate is seen. h Invasive breast cancer- malignant cells have invaded the surrounding stromal tissues. i Lymph node metastasis

Figure 2

Stromal alterations in breast cancer progression. a In phenotypically normal tissue, epithelial structures consist of central luminal epithelial cells encircled by myoepithelial cells and enclosed by a continuous basement membrane, while the primarily collagenous stroma contains fibroblasts, immune cells, and vasculature. b Progression to carcinoma in situ is characterized by proliferative epithelial cells enclosed in a still-continuous basement membrane, increased numbers of fibroblasts and immune cell infiltrate, and enhanced angiogenesis. c Invasive breast carcinoma is defined by breakdown of the basement membrane, loss of myoepithelial cells, and invasion of the tumor cells into the surrounding stroma and the vasculature

Figure 3

Transcriptional profiling of stromal alterations. Slides from breast tissue biopsies are microdissected to separate the proliferative epithelial cells from the surrounding stroma. RNA is extracted from the tissue slides and analyzed by microarray; comparison of transcriptional profiles from patients who subsequently progressed to invasive breast cancer with profiles from patients who did not progress can reveal transcripts prognostic for breast cancer progression