**4. Breast cancer progression models**

The combined research efforts of various scientific disciplines have resulted in the develop‐ ment of a disease progression model for breast cancer (See Figure 1) and include a continuum of lesions through to invasive carcinoma and eventually metastatic disease [30, 48, 67, 68]. For decades, it was thought that metastatic dissemination occurred as a final step in cancer and was the responsibility of genetic changes of malignant cells in the primary tumor [69]. In 2008, Husemann *et al*, used transgenic mice to show systemic dissemination (specifically to lungs and bone marrow) of mammary tissue derived premalignant cells prior to the emergence of mammary tumors [70]. Additionally, this research reported that systemic dissemination of tumor cells can occur in pre-invasive stages of tumor progression as observed in female patients with ductal carcinoma *in situ*. A complementary accumulation of evidence supports the evolution of an early dissemination model, where malignant cells outside the primary lesion can also migrate to distal sites (such as lung and bone marrow) and cause tumors via various genetic programs [54, 71, 72]. Such a model is inclusive to "self-seeding", the term coined when cancer cells not only seeds regional (lymph nodes) and distant sites but also fuel the growth of the original tumor itself [73].

**Figure 1. (Tobin, GA, 2011) Physiological Aspects of Disease Progression in Breast Cancer:** The development of breast cancer has been proposed as a multi-step process. The most deadly aspect of breast cancer is metastasis and involves a cascade of reactions. Although the molecular mechanisms underlying this process are not fully understood, any disruption along the cascade could arrest disease progression.

Thus, breast cancer is not a single disease, but rather an assortment of diseases with diverse characteristics and clinical outcomes which will likely always require a variety and/or combination of treatments or alternatively, a broad spectrum application. Combine this with the fact that, despite major advances in our understanding of the biology of cancer, further research is required to improve our understanding of tumor establishment, progression and dissemination - the principal cause of mortality. Then, our goal in breast cancer research regarding treatment would be to identify novel therapies and maximize, based on our current understanding of the disease, the use of such in preventing and treating as many aspects of the disease as possible.
