How Obesity Promotes Breast Cancer

Regular readers of these pages are probably well aware of the increasing data on the importance of obesity as a risk factor for cancers.

This is particularly true for hormone-sensitive cancers like post-menopausal breast and ovarian cancer, which are significantly more common in women with excess weight. In addition, excess weight appears to negatively affect the prognosis and recurrence of these cancers irrespective of menopausal status.

One of the key genetic factors associated with breast and ovarian cancers is the tumor suppressor gene BRCA1, which plays an important role in DNA repair. Women who carry mutations in this gene have a 80% lifetime risk of breast cancer – but reduced activity of BRCA1 has also been found in cancers of women who do not carry BRCA1 mutations.

So can excess weight modify expression of BRCA1?

A new study by Li-Jun Di and colleagues from the US National Cancer Institute, Bethesda, ML, published in the latest issue of Nature Structural & Molecular Biology, now shows that the expression of the BRCA1 is regulated by a co-repressor and metabolic sensor called C terminal-binding protein (CtBP), which is in turn regulated by energy levels in a cell.

Simply put, when cells see too many calories, CtBP can switch off BRCA1 thereby negatively influencing DNA repair.

This situation is particularly harmful for tissues like the breast or ovaries which, in obesity, are at the same time stimulated by excess activation of estrogen in fat tissue.

Thus, excess weight not only causes breast and ovarian tissue to grow but at the same time it indirectly inhibits one of the key DNA repair molecules, thereby making it far more likely that mutations will cause malignant growth of these cells.

As recently discussed in another post, this is another example that the strong link between excess weight and cancers may not lie in the excess weight causing genetic defects, but rather in the weight affecting important repair mechanisms that would normally protect against cancers.

These observations certainly help explain the dramatic decrease in cancer risk seen with intentional weight loss in patients undergoing bariatric surgery.

Toronto, Ontario (in transit)

Di LJ, Fernandez AG, De Siervi A, Longo DL, & Gardner K (2010). Transcriptional regulation of BRCA1 expression by a metabolic switch. Nature structural & molecular biology PMID: 21102443