Molecular Aspects of Breast Cancer Metastasis to the Brain

Abstract

Our knowledge of the biology underlying the development of brain metastases (BM) from breast cancer has improved over the last decade due to large clinical epidemiological studies, animal models of metastasis, and the use of high-resolution gene expression profiling technologies. However, there are still major gaps in our understanding of the mechanisms utilized by breast cancer cells to colonize the brain microenvironment, thus our arsenal of therapies remains relatively nonspecific, and the prognosis for breast cancer patients with BM remains poor. Additional insights into these mechanisms are necessary to facilitate the development of new preventive and curative therapeutic regimens to block this fatal disease. This paper aims to provide a general overview for the readers of what has been achieved in this field of research and its translation into clinical practice to date and to highlight exciting new areas of research that promise to inform the development of new targeted therapies for BM.

Inhibition of Type I Insulin-Like Growth Factor Receptor Signaling Attenuates the Development of Breast Cancer Brain Metastasis

“…Approximately 10-16% of breast cancer patients develop brain metastases, and this continues to be a major cause of mortality in women [1,2,4,5]. The mean survival of patients with brain metastases ranges from 3–18 months, with a one-year survival rate of 20% [4,6,7].…”

Numerical aberrations of chromosome 17 and TP53 in brain metastases derived from breast cancer

“…Breast cancer is a heterogeneous disease with respect to molecular features, which is perhaps best exemplified by the molecular subgroups identifiable by gene expression profiling including basal-like, luminal A (hormone receptor positive), luminal B, and human epidermal growth factor receptor 2 (HER2) amplified/over-expressed (HER2+) subtypes (Saunus et al, 2011). It has been demonstrated that primary breast cancer with a basal-like immunophenotype has the propensity to metastasize to the brain (Espinosa et al, 2006).…”

“…The most common primary metastatic sites in adults are the lung (35%), central nervous system (CNS; 25-30%) and breast (14-18%; Weil et al, 2005;Cambruzzi et al, 2011;Saunus et al, 2011). This phenomenon is called organotropism, which means that the distribution of metastasis in different organs is nonrandom; i.e., the tumor cells could have specific affinity for the microenvironments of certain organs (Talmadge and Fidler, 2010;Saunus et al, 2011).…”

“…This phenomenon is called organotropism, which means that the distribution of metastasis in different organs is nonrandom; i.e., the tumor cells could have specific affinity for the microenvironments of certain organs (Talmadge and Fidler, 2010;Saunus et al, 2011). Organotropism was first described by Paget (1889) after studying autopsy records of 735 women with breast cancer.…”

“…Tumor metastasis is a multistage process in which malignant cells spread from a primary tumor to distant organs via the blood and/or lymphatic system (Fidler, 2003;Talmadge and Fidler, 2010;Saunus et al, 2011). Of the approximately 1.3 million people diagnosed with cancer in the United States each year, approximately 100,000 to 170,000 will develop brain metastases; this corresponds to an annual incidence of around 4.1 to 11.1 per 100,000 individuals (Barnholtz-Sloan et al, 2004;Cambruzzi et al, 2011).…”