Triple-negative breast cancer risk in women is defined by the defect of estrogen signaling: preventive and therapeutic implications

Abstract

Epidemiologic studies strongly support that triple-negative breast cancers (TNBCs) may be distinct entities as compared with estrogen receptor (ER)+ tumors, suggesting that the etiologic factors, clinical characteristics, and therapeutic possibilities may vary by molecular subtypes. Many investigations propose that reproductive factors and exogenous hormone use differently or even quite inversely affect the risk of TNBCs and ER+ cancers. Controversies concerning the exact role of even the same risk factor in TNBC development justify that the biological mechanisms behind the initiation of both TNBCs and non-TNBCs are completely obscure. To arrive at a comprehensive understanding of the etiology of different breast cancer subtypes, we should also reconsider our traditional concepts and beliefs regarding cancer risk factors. Malignancies are multicausal, but the disturbance of proper estrogen signaling seems to be a crucial risk factor for the development of mammary cancers. The grade of defect in metabolic and hormonal equilibrium is directly associated with TNBC risk for women during their whole life. Inverse impact of menopausal status or parity on the development of ER+ and ER- breast cancers may not be possible; these controversial results derive from the misinterpretation of percentage-based statistical evaluations. Exogenous or parity-associated excessive estrogen supply is suppressive against breast cancer, though the lower the ER expression of tumors, the weaker the anticancer capacity. In women, the most important preventive strategy against breast cancers - included TNBCs - is the strict control and maintenance of hormonal equilibrium from early adolescence through the whole lifetime, particularly during the periods of great hormonal changes.

Keywords: cancer prevention; infertility; insulin resistance; menopause; metabolic syndrome; type 2 diabetes.

Figure 1

Graphic representation of age-related increases in overall ER+ and ER− BC incidences. Notes: Raw numbers show a close to twofold increase in ER− tumors and a much higher – almost fourfold – increase in ER+ tumors with aging, while the percentage of ER− cancers exhibits a decreasing trend. Data derived from Hartley et al. Abbreviations: BC, breast cancer; ER, estrogen receptor.