Pathophysiology of the Link Between Obesity and Breast Cancer

Obesity is a known risk factor for the development of many cancers in women. Obese women have a higher risk of developing breast cancer and have altered treatment and health outcomes as a result of this increased body mass.

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In both pre- and postmenopausal women, increased body weight is a risk factor for oncogenesis in the breast. However, it is believed that this increase in body weight is protective in very young premenopausal women with a negative family history who live in developed nations.

Further, more fatty tissue is thought to have a favorable effect when the diagnosis of breast cancer is made at a more advanced stage with more widespread or more aggressive tumors. Nonetheless, survival is generally poorer in obese women of all ages.

Factors related to obesity in breast cancer

Estrogen

An increase in body fat is related to a greater risk of postmenopausal cancer rather than the body mass index (BMI), body weight, and visceral or abdominal fat. In fact, this correlation has found that there is up to a 45% greater chance that women with higher body fat will develop postmenopausal cancer.

This parameter is related to increased estrogen levels in the form of estrone, estradiol, and free hormone levels. In premenopausal women, this relationship is unclear because the ovary is the chief source of estrogens.

Comparatively, in postmenopausal women, estrogen is produced in peripheral adipose tissue via the aromatase enzyme, which is richly found in breast fatty tissue and tumor cells. This enzyme converts adrenal and ovarian androgens into estrogens.

The local activity of this aromatase enzyme leads to higher local concentrations of estrogens in the tumor, which is believed to be regulated, to some extent, by the cytokines tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6).  These cytokines can act in either a positive or negative manner to increase or decrease aromatase activity, which is also regulated by the use of aromatase inhibitors in the treatment of breast cancer.

Estrogen levels are 15% higher, on average, in women with postmenopausal breast cancer. Moreover, the cancer risk is doubled at the highest levels, especially in those with both estrogen and progesterone receptors. Any increase in mean serum estrogens is associated with a higher risk of breast cancer according to recent findings.

The relationship between estrogen and hormone receptors is important in breast cancer treatment, as well as in determining treatment outcomes. Estrogen and progesterone receptors, as well as the human epidermal growth factor receptor 2, are active in many of these tumors.

The estrogen receptors-α (ER-α) promote cell proliferation, whereas ER-β are associated with better outcomes. Thus, the ER+/- status of a tumor refers primarily to the presence of ER-α receptors. ER positivity is more common in obese postmenopausal women and those with a history of weight gain between 20 and 50 years.

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Other receptors

Progesterone receptors (PR) are also of two forms, PR-A and PR-B, both of which are activated by the same gene but mediated by different promoters. Both PR-a and PR-B are therefore referred to as PR and their positivity is related to obesity in postmenopausal women. It is notable that receptor concentrations are directly related to the amount of weight gained, particularly in adult life.

Human epidermal growth factor receptors-2 (HER-2) bind a growth receptor, which promotes tumor cell proliferation and therefore indicates aggressiveness. The level of this receptor is reduced with increasing obesity in postmenopausal, but not premenopausal women.

On the other hand, when measured in association with PR, the correlation was positive for body weight. This may indicate that the hormone receptors are more important than HER-2 in early tumor growth, but this becomes negative as the tumors continue to grow.

Weight reduction in obese subjects reduces estrogen levels in the blood and increases the concentration of sex hormone binding globulin (SHBG) in the blood. A recent study showed an 85% reduction in breast cancer incidence following obesity reduction by gastric bypass surgery.

Insulin

Obesity is associated with insulin resistance and hyperinsulinemia, which mediates its growth-promoting activities via insulin-like growth factor-1 (IGF-1) and IGF-binding proteins. It also is associated with oxidative and inflammatory stress, endocrine dysfunction, and immunologic abnormalities, all of which promote tumor development.

Leptin

Leptin, which is a protein that is produced from fat cells, is found in elevated concentrations in obese individuals. In addition to leptin, its receptor is present along with ER-α in cancer cells that have been derived from breast cancer lines.

Different isoforms are expressed on ER+ and ER- cell lines. Leptin is a promoter of cell proliferation. There is an increased expression of aromatase and thus increased estrogen synthesis.

Adiponectin

Adiponectin is a protein that is reduced in obese subjects, with its receptors found on both ER+ and ER- cell lines from human breast cancer. Moreover, this protien is an inhibitor of cell proliferation in ER+ lines at a lower concentration. Adiponectin may also promote apoptosis in breast cancer cells.

References

Further Reading

Last Updated: May 12, 2021

Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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