The identification of a signalling protein that regulates the accumulation of fat and connective tissue in breasts may help to explain why high mammographic density is linked to breast-cancer risk. It may also provide a marker for predicting this risk.
Our ability to evaluate the lifetime risk of breast cancer in women who have a family history of breast and ovarian cancer was revolutionized by the identification1 of the breast-cancer-associated genes BRCA1 and BRCA2. But although this was a landmark discovery, it has not translated into improvements in the assessment of breast-cancer risk in the general population2, because more than 95% of women who develop breast cancer do not have a BRCA-gene mutation3. So the search for biomarkers to predict the risk in these women remains a goal for many biologists, clinicians and epidemiologists.
Over the past decade, increased mammographic density — thought to result primarily from an increased proportion of breast collagen content relative to fat-tissue content4,5 — has emerged as a non-genetic marker of breast-cancer risk6. However, the biological mechanism that relates tissue density to tumour development is poorly defined. Writing in Cancer Discovery, DeFilippis et al.7 now provide a link between mammographic density and cellular signalling during the initiation of breast cancer.
The human breast is composed of many cell types, including connective-tissue (stromal) cells, fat cells (adipocytes), cells that make up blood vessels (endothelial cells) and immune cells. Collectively, these cells make up the microenvironment of the breast8. Over the past five years, it has been increasingly recognized that this microenvironment, including the relative proportions of different types of cell and therefore the tissue density, may have a major role in the initiation and progression of breast cancer9,10. One indication of this role is the epidemiological link between mammographic density and cancer risk: Caucasian women with high mammographic density have a two- to sixfold increase in lifetime risk of developing breast cancer6. Another indication is the physical change in the breast microenvironment that is seen in the initial stages of breast-tumour formation. This is described as a desmoplastic reaction, which is characterized by the recruitment and activation of stromal cells and results in increased collagen deposition in the breast — and therefore increased mammographic density11.
The increased density is measured by a general increase in X-ray absorbance and is therefore relatively inexpensive and easy to measure. But we have little understanding of what determines increased density and how this is linked to increased cancer risk and the initiation of tumour formation4,6. The situation is complicated by the complex relationships between mammographic density, breast-cancer risk, ageing, obesity and race. For example, mammographic density typically declines with age12, but, because breast cancer is an age-related disease, this means that, paradoxically, a woman's breast-cancer risk will increase with age while her mammographic density declines.
DeFilippis and colleagues have helped to unravel this story by revealing that expression of a single molecule, CD36, is necessary and sufficient to regulate two key features of mammographic density: the number of adipocytes in the breast and the amount of collagen deposited in the breast tissue. The authors show that expression of CD36 is lower in breast-tissue cells of women with high mammographic density — in women with or without breast cancer — than in cells from breasts with normal density (Fig. 1). CD36 is an integral membrane protein found in many cell types, and it is already known to regulate several basic cellular processes governing how cells interact and grow, including the differentiation of adipocytes, the growth of new blood vessels (angiogenesis) and immune signalling13. Now it seems that an influence on mammographic density can be added to this list.
To establish how CD36 expression exerts its effects on breast-tissue density, the authors modulated CD36 expression in vitro in cells taken from healthy human breast tissue. They found that reducing CD36 expression led to a decrease in the total number of fat cells and an increase in the amount of collagen deposited in the extracellular matrix around the cells; higher CD36 expression increased the number of fat cells (Fig. 1). The researchers also observed lower fat accumulation and greater collagen accumulation in the mammary glands of mice lacking the Cd36 gene. These findings indicate that inhibition of this protein is sufficient to recapitulate some of the key events that lead to higher mammographic density and initiation of breast cancer.
Not only do these findings provide a mechanistic link between cell-signalling pathways and mammographic density, they are also a convincing indication that loss of CD36 may be an early event in breast carcinogenesis. Although mammographic density is used as a surrogate marker of breast-cancer risk in the general population, it is an imprecise indicator. It gives little insight into the biology of why a woman might develop breast cancer, and it is confounded by paradoxes, such as the increase in density but decrease in risk if a woman exercises, or the decrease in density but increase in risk as a woman ages. By demonstrating that CD36 links the biology of breast density with the biology of breast-cancer initiation, DeFillipis and colleagues have provided information that may help to make density a more useful marker of risk. Finally, their results also raise the possibility that CD36 could be pharmacologically targeted in attempts to prevent breast cancer in the majority of women who (fortunately) lack a BRCA mutation.
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