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Breast cancer is the second most common cancer worldwide after lung cancer, the fifth most  common cause of cancer death, and the leading  cause of cancer death in women. the global burden of  breast cancer exceeds all other cancers and the incidence  rates of breast cancer are increasing (1,2).

The heterogeneity of breast cancers makes them both a fascinating and challenging solid tumor to diagnose and treat. Here is a great review of the molecular pathology of breast cancer progression (3).

“The molecular pathology of breast cancer progression” by Alessandro Bombonati  and Dennis C Sgroi.

Breast cancer is the most frequent carcinoma in females and the second most common cause of cancer related mortality in women. Approximately 54 000 and 207 000 new cases of in situ and invasive breast carcinoma, respectively. Overall, breast cancer incidence rates have levelled off since 1990, with a decrease of 3.5%/year from 2001 to 2004.  Most notably, during this same time period, breast cancer mortality rates have declined 24%, with the largest impact among young women and women with estrogen receptor (ER)-positive disease.

The decline in breast cancer mortality has been attributed to the combination of early detection with screening programmes and the advent of more efficacious adjuvant progression have aided in the discovery of novel pathway-specific targeted therapeutics, and the emergence of such effective therapeutics is currently driving the need for molecular-based, ‘patient-tailored’ treatment planning.

Proposed models of human breast cancer progression

Epidemiological and morp

hological observations led to the formulation of several linear models of breast cancer initiation, transformation and

progression. Figure 1

The ductal and lobular subtypes constitute the majority of all breast cancers worldwide, with the ductal subtype accounting for 40–75% of all diagnosed cases.

The classic model of breast cancer progression of the ductal type proposes thatneoplastic evolution initiates in normal epithelium (normal), progresses to flat epithelial atypia (FEA), advances to atypical ductalhyperplasia (ADH), evolves to ductal carcinoma in situ (DCIS) and culminates as invasive ductal carcinoma (IDC).

The model of lobular neoplasia proposes a multi-step progression from normal epithelium to atypicallobular hyperplasia, lobular carcinoma in situ (LCIS) and invasive lobular carcinoma (ILC).

The cell of origin of breast cancer: the clonal and stem cell hypotheses

The two leading models accounting for breast carcinogenesis are the sporadic clonal evolution model and the cancer stem cell (cSC) model. According to the sporadic clonal evolution hypothesis, any breast epithelial cell can be the target of random mutations. The cells with advantageous genetic and epigenetic alterations are selected over time to contribute to tumour progression. The third alternative cSC model postulates that only stem and progenitor cells (representing a small fraction of the tumor cells within the cancer) can initiate and maintain tumor progression. Figure 2.

Normal breast stem cells (nBSCs) are long-lived, tissue-resident cells capable of self-renewal activity and multi-lineage differentiation that can recapitulate the breast tubulolobular architecture that is composed of luminal and myoepithelial cells.

As normal breast cancer stem cells are long-time tissue residents, it has been proposed that such cells are candidates for accumulating genetic and epigenetic modifications. It has been further proposed that such molecular alterations result in deregulation of normal self-renewal, leading to the development of a cancer stem cell (cSC).

It is believed that the cSC undergoes asymmetrical division, maintaining the stem cell population while at the same time differentiating into committed progenitor(s) cells that give rise to the different breast cancer subtypes.

A second scenario, as it relates to breast cancer development, is one in which the cancer-initiating cells are derived from committed progenitor cells that spawn different breast cancer subtypes. Both scenarios are highly supported.

Molecular analysis of the different stages of breast cancer progression

Genomic and transcriptomic data in combination with morphological and immunohistochemical data stratify the majority of breast cancers into a “low-grade-like” molecular pathway and a “high-grade-like” molecular pathway. Figure 3. The low-grade-like pathway (left hand side) is characterized by recurrent chromosomal loss of 16q, gains of 1q, a low-grade-like gene expression signature, and the expression of estrogen and progesterone receptors (ER+ and PR+). The progression (vertical arrows) along this pathway (green rectangles) culminates with the formation of low and intermediate grade invasive ductal, (LG IDC and IG IDC) and invasive lobular carcinomas including both the classic (ILC) and the pleomorphic variant (pILC). The tumors arising from the low grade pathway are classified as luminal consisting of a continuum of gene expression frequently associated with the absence (luminal A) or presence of HER2 expression (luminal B). The vast majority of ILCs and pILCs and their precursors cluster together within the luminal subtype. The high grade-like gene expression molecular pathway (right hand side) is characterized by recurrent gain of 11q13 (+11q13), loss of 13q (13q−), expression of a high-grade-like gene expression signature, amplification of 17q12 (17q12AMP), and lack of estrogen and progesterone receptors expression (ER− and PR−). The progression along this pathway (red rectangles) includes intermediate and high grade ductal carcinomas that are stratified as HER2, or basal-like, depending on the expression/amplification of HER2. The molecular apocrine subtype, characterized by the lack of ER expression and presence of AR expression, arises from the high grade pathway. The model also depicts intra-pathway tumor grade progression (horizontal arrows).

Although the genomic and transcriptomic data presented in this review support the divergent model of breast cancer progression, the clinical experience indicates that tumors within each pathway are still fairly heterogeneous with respect to clinical outcome suggesting that even this advanced molecular progression scheme is oversimplified.

The future application of massively parallel sequencing technologies to the preinvasive stages of breast cancer will assist in assessing intratumoral heterogeneity during the transition from preinvasive to invasive breast cancer, and may assist in identifying early tumor initiating genetic events.

Summary:

Over the past decade the integration of numerous genomic and transcriptomic analyses of the various stages of breast cancer has generated multiple novel insights in the complex process of breast cancer progression.

• First, human breast cancer appears to progress along two distinct molecular genetic pathways that strongly associate with tumor grade.
• Second, in the epithelial and non-epithelial components of the tumor microenvironment, the greatest molecular alterations (at the gene expression level) occur prior to local invasion.
• Third, in the epithelial compartment, no major additional gene expression changes occur between the preinvasive and invasive stages of breast cancer.
• Fourth, the non-epithelial compartment of the tumor micromilieu undergoes dramatic epigenetic and gene expression alterations occur during the transition form preinvasive to invasive disease. Despite these significant advances, we have only begun to scratch the surface of this multifaceted biological process. With the advent of additional novel high-throughput genetic, epigenetic and proteomic technologies, it is anticipated that the next decade of breast cancer research will gain an equally paralleled appreciation for the complexity breast cancer progression. It is with great hope that knowledge gained from such studies will provide for more effective strategies to not only treat, but also prevent breast cancer.

Ref:

1. http://www.nature.com/nrclinonc/journal/v7/n12/pdf/nrclinonc.2010.192.pdf

2. Jemal, a. et al. CA Cancer J. Clin. 60, 277–300; 2010

3. Alessandro Bombonati and Dennis C Sgro. The molecular pathology of breast cancer progression. J Pathol 2011; 223: 307–317.

http://onlinelibrary.wiley.com/doi/10.1002/path.2808/pdf

http://pubmedcentralcanada.ca/pmcc/articles/PMC3069504/

4. Rodney C. Richie and John O. Swanson. Breast Cancer: A Review of the Literature. J Insur Med 2003;35:85–101.