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The Molecular Biology of Breast Cancer
Acknowledgments
This work was supported in part by research grants from the NIH/National Cancer Institute R01CA94118 (AVL), R01097213 (SO), the Breast Cancer Research Foundation (SO and NED), Susan G. Komen for the Cure (AVL), the Pennsylvania Department of Health (AVL and SO), and the Pennsylvania Breast Cancer Coalition (SO).
Molecular Biology of Breast Cancer Initiation and Progression
Normal Breast Development
Studies of breast cancer from the 1970s to the mid-1990s focused mainly on changes in breast cancer with little regard for normal tissue or development. A lack of knowledge of normal mammary gland development and function limited the understanding of tumor-specific changes. In 1998, the NCI-directed Breast Cancer Progress Review Group stated, “Our limited understanding of the biology and developmental genetics of the normal mammary gland is a barrier to progress.” This statement led to a major increase in such studies, with mouse models giving invaluable insights into the molecular biology of both normal mammary gland development and breast cancer. Extensive genetic and molecular analysis of mammary gland development in small and large animals has rapidly defined many of the intricate molecular networks, such as interactions between steroid hormone and growth factors, that are critical for all stages of development and function. Intriguingly, many of these same pathways have major roles in breast cancer development and progression and thus are major therapeutic targets. One of the greatest advances has been the recent identification and characterization of mouse mammary stem cells. Sorting cell populations using cell surface markers has shown that the myoepithelial cell layer contains adult mammary stem cells and that a single cell transplanted into the mouse can produce every epithelial cell of the mammary gland. Evidence that mammary stem cell number and function are regulated by hormones such as progesterone and RANK ligand is consistent with the major functions of hormones in mammary gland function and may have implications for human breast cancer development and treatment. Intriguingly, BRCA1 has also been found to regulate mammary stem cell number and function, and evidence suggests that BRCA1 cancers may arise from a blockade of progenitor cell development.
Clonal and Stem Cell Hypotheses
There are two main models for cancer initiation and progression, the clonal evolution hypothesis and the cancer stem cell (CSC) hypothesis. In the clonal evolution hypothesis, any cell is susceptible to sporadic random mutation, and a particular combination of mutations allows selection of a cell to evolve to become immortal and tumorigenic. Thus any cell within a tumor can maintain tumorigenesis. In contrast, the CSC hypothesis posits that only stem and progenitor cells, which are a minor fraction of cells within a tumor, can give rise to self-renewing tumor cells. These two hypotheses have major implications for understanding breast cancer development and therapeutic intervention. However, the two hypotheses both rely on major assumptions that are virtually impossible to assess, given the inherent difficulty in tracking cell transformation and differentiation in human breast tumors. Although both hypotheses are often presented as competing ideas, it is highly likely that tumorigenesis is a combination of both models. Future studies will be required to define cancer cell growth and differentiation and better define the role of clonal and cancer stem cell function, as this will likely have major implications for the prevention and treatment of the disease.
Preneoplastic Progression
Advances in molecular biology have had a major impact in the understanding of premalignant progression. Early studies using anatomic pathology and epidemiology revealed that certain premalignant breast lesions such as atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) were associated with an increased risk of developing subsequent invasive ductal cancer (IDC). Analysis of changes in DNA copy number and loss of heterozygosity showed that synchronous and metachronous DCIS and IDC showed almost identical genetic changes indicating that DCIS is the precursor for IDC. Consistent with this, the diversity of transcriptomic change and IDC subtypes is similarly found in DCIS. Although 80% to 90% of breast cancer is of ductal origin, a smaller percentage (but still large number of breast cancers) are of lobular origin. These are much less studied; however a similar pattern of progression from atypical lobular hyperplasia to lobular carcinoma in situ to invasive lobular cancer is thought to occur.
Pathophysiology and Risk Factors
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