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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.

AMS
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

6 Comments

  1. Would it not be better to acknowledge that glucose and fructose promote both obesity and cancer. If anyone is serious about reducing the risk of both (also reducing blood sugar, insulin), stop eating sugar in any form and grains in any form (high caloric density food with no (little) nutritional value). It will be easier to stop eating these if you stop manufactured oils as well. Those three seem to hold hands.

    Keep up the fine work.

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  2. Great Post! I found the information interesting and a bit alarming. Thanks for keeping us informed. Is there testing available to women to find out if she carries mutations in the gene BRCA1?

    P.S. If any of you are looking to lose some weight, you should check out my little page that I set up to help you! http://successfulweightlossarticals.blogspot.com

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  3. This kind of information makes me feel condemned to ill health. I am a so-called obese person, and while I am healthy at the moment, most of what I read suggests that I am a ticking time bomb.

    Other than bariatric surgery, I haven’t really heard of any effective approaches to losing a lot of weight (I would have to lose 70 lbs to arrive at a BMI that is just under 25) and keeping it off permanently. Since I’m probably not a candidate for bariatric surgery, and I already have a healthy lifestyle, I supposed I’ll just have to hope for the best. Or should I embark on (another) diet anyway and hope I won’t gain the weight back?

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  4. @Jennifer: No one is condemned. Eating healthy and getting enough exercise is the best way to counteract the negative impact of excess weight. Rather than a new diet, I would suggest focussing on being the healthiest at the best weight you can happily maintain.

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  5. Talking about breast cancer and obesity, we must differentiate between premenopausal and menopausal obese women. Since the increased risk of breast cancer and obesity has been associated with postmenopausal women (with no hormone replacement therapy), This is due to the fact during menopause, fat acts as an important source synthesizing estrogen (by interconversion) ) thus generating a greater percentage of circulating estrogen. This greater estrogen content will increase cancer exposure in those tissues which are more sensible such as breast tissues.

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