Obesity fuels breast carcinogenesis: What is the molecular basis?





Obesity has become a major health problem in all societies. Obesity rates have risen 30% in Saudi Arabia over the last 10 years; with nearly 50% of women and 40% of men are obese. Many epidemiological studies have indicated a positive association between obesity and an increased risk of various types of cancers including breast. Growing evidence also suggests that breast cancers that occur in obese women are more aggressive and less responsive to various treatments, and that women who are overweight or obese at the time of diagnosis are at higher risk of cancer recurrence and death compared with leaner women. There are also some indications that gain of weight after breast cancer diagnosis may also lead to poor outcomes. A previous study conducted at the King Faisal Specialist Hospital & Research Center found a strong link between obesity and breast cancer among Saudi women. Indeed, seventy percent (70%) of patients with this malignant disease were obese at diagnosis.

Several hypotheses and theories have been proposed, however, the molecular mechanisms that underlie the link between obesity and this deadly disease still remain elusive.

A research team at the King Faisal Specialist Hospital & Research Center led by Dr. Abdelilah Aboussekhra, Principle Scientist and Chairman of the Department of Molecular Oncology at the Research Center, conducted a mechanistic study aiming at elucidating the molecular/genetic basis of the link between obesity and breast cancer risk. The study began with the collection of samples of fatty
breast tissue from obese women (BMI ≥30) and others with normal weights (BMI <30) who underwent plastic breast reduction. The fatty cells (adipocytes) were then utilized for cellular and molecular analysis.

The research team observed a remarkable link between obesity and the molecular as well as the cellular features of these cells. Indeed, breast adipocytes extracted from obese women expressed low level of the tumor suppressor protein (p16) and were more proliferative, migratory, invasive and procarcinogenic as compared to those developed from lean women. To shed more light on the potential of obesity in promoting breast carcinogenesis, the team underwent in situ experiments, which provided the first indication that breast tissues from obese females contain epithelial cells with features of breast cancer cells. This confirmed the susceptibility of these cells, which can be transformed into cancer, to the effects of their microenvironment and their predisposition for randomized obesity-related neoplastic transformation.

In addition, using state of the art techniques, it has been shown that the p16 protein represses the expression/secretion of the obesity-related procarcinogenic protein called leptin (LEP) from the adipocytes. Therefore, p16-deficient adipocytes as well as those derived from obese women stimulated
the carcinogenesis process in normal epithelial breast cells derived from thin women, as well as accelerated the growth of cancer in mice.

"These findings shed more light on the relationship between obesity and breast cancer and indicate the risk of excessive weight gain," said Dr. Huda Al-Khalaf, a senior researcher in this study who works as Associate Professor at King Abdulaziz City for Science and Technology. She also confirmed that this study will pave the way toward understanding the cellular and molecular basis of the link between obesity and other types of cancers, which will have a great impact on the awareness and prevention programs. Indeed, the present study provides clear molecular evidence that controlling body weight will help preventing carcinogenesis.

It is noteworthy that this study is the result of a fruitful collaboration with several clinicians at the King Faisal Specialist Hospital and the Research Center in Riyadh, Mohamed Mrad (Plastic Surgeon), Dr. Asma Tulbah (Consultant Pathologist) and Dr. Adher AlSyed (Consultant Oncologist) and with the help of Dr. Falah Al-Muhanna (Veterinarian, Department of Comparative Medicine). These findings were recently published in the leading scientific journal in the field of cellular and molecular research (Molecular and Cell Biology), issued by the American Society for Microbiology.

The research team expressed their sincere gratitude to the Research Center administration at King Faisal Specialist Hospital and Research Center for their continuous support and to all the patients who contributed in the success of this study.