Breast Cancer

Carcinoma of the breast is the most common nonskin malignancy in women, exceeded only by lung cancer as the greatest cause of cancer deaths in women. The major known risk factors are hormonal and genetic (family history). Chronological age is the strongest predictor of nongenetic risk; a woman who lives to age 90 has a one in eight chance of developing the disease. Hormonally based risk factors include age of menarche, age of first live birth, and first-degree relatives with breast cancer. Of breast cancer with a genetic basis, about 25 percent can be attributed to two autosomal-dominant genes, BRCA1 and BRCA 2; however, inherited mutations at these loci account for only about 3 percent of all breast cancers. Thus, sporadic breast cancer is by far more common than familial, and risk increases with exposure to excess estrogen stimulation, especially in cells that express the estrogen receptor (ER).

Transformation from normal to malignant phenotype requires that the deoxyribonucleic acid (DNA) become damaged and unstable (initiation), and that damaged cells be exposed to growth stimulants in a permissive environment that allows unrestrained proliferation (promotion and progression). Estrogen plays at least two roles in this process: (1) metabolites of estrogen can cause DNA mutations and DNA damage, and (2) estrogens act as growth promoters, driving premalignant proliferation. A subset of breast carcinomas do not express the estrogen receptor (ER negative); however, it is not certain whether these cells were initially estrogen independent or became neoplastic under the influence of estrogens and converted to an ER-independent phenotype in a later phase.

Obesity, Circulating Hormones, and Postmenopausal Breast Cancer

Three major hypothesis have been advanced to explain the observed association between obesity and postmenopausal, but not premenopausal breast cancer. The first is that elevated concentrations of circulating estrogen metabolites found in obese women and men expose breast tissue to excess hormone. While ovarian estrogen synthesis is the major source of estrogen in the premenopausal women, estrogen metabolites are also formed by peripheral conversion of adrenal androgens in adipose tissue in the breast, abdomen, thighs, and buttocks. As indicated above, chronic estrogen exposure has potential both to initiate and promote breast cancer. Alternatively, metabolic syndrome, associated with obesity, elevated circulating concentrations of insulin, insulin-like growth factors, glucose, and triglyceride-rich lipoproteins can provide an anabolic environment conducive to neoplastic growth. Cross-talk potentiation between insulin and the estrogen receptor pathway has been postulated; increased signaling through this pathway can directly activate gene transcription and secondary signaling pathways within the cell. Because hyperinsulinemia has been associated with risk for recurrence and mortality from breast cancer regardless of its ER status, other pathways must also be involved.

Magnified breast cancer: While breast cancer is often caused by genetic factors, doctors have discovered a link to obesity as well.

Adipocyte as Endocrine Tumor

Adipocyte metabolism has also been linked to the development of breast cancer. Adipocyte is an endocrine organ that secretes factors that both act locally in paracrine fashion, and enter the circulation. Mature adipocytes secrete leptin, known to regulate food intake and energy balance. Breast tissue does not normally express leptin receptors, but the presence of leptin receptors on a breast tumor is associated with lower survival and distant metastases. Inflammatory cytokines including tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are also synthesized and secreted by adipocytes and adipose tissue-associated [Page 96]macrophages. These cytokines have diverse activities, including cell signaling and control of dendritic cell growth, which have potential to regulate connective tissue integrity and control the degree of tumor invasion. Undifferentiated preadipocytes secrete estrogen metabolites through the action of aromatase, an enzyme that converts adrenal androgens to estrogens. Control of this enzyme is poorly understood, but it is known to respond to signals from mature adipocytes, including TNF-α and IL-6. Aromatase activity can elevate the local estrogen concentration manyfold, increasing exposure of breast tissue to this potential carcinogen and growth promoter.

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