Estrogen receptor implications in human pancreatic cancer

The sex steroid estrogen, androgen and progestin hormones all play a functional role in the healthy pancreas. Pancreatic cancer, a highly lethal disease, has a higher prevalence in men compared to women. While these factors may suggest a potential role for sex hormone regulation or dysregulation in pancreatic carcinogenesis, the majority of epidemiological studies have failed to support an association between hormonal factors and pancreatic cancer development. Similarly, hormonal manipulation with the antiestrogen tamoxifen as a therapeutic strategy for pancreatic cancer has been explored clinically, but was met with limited success. Nevertheless, recent studies show that human pancreatic cancers express two subtypes of estrogen receptor (ER), namely ER α and ER β each ER subtype is capable of distinct estrogenic signaling, thus corroborating a role for estrogens in human pancreatic cancer. Furthermore, the ratio of ER β to ER α mRNA level is significantly higher in pancreatic cancer tissues compared to ER-positive as well as ER-negative breast cancers, and several human pancreatic cells have greater ER β protein expression than ER α, suggesting that the ratio of ER α to ER β may be a specific determinant of pancreatic cancer pathology. The focus of this review is to consider the implications of the ER expression on pancreatic cancer responsiveness to selective estrogen receptor modulators (SERMs). The usefulness of androgen and progesterone receptor modulators in pancreatic cancer treatment is also reviewed briefly. All aspects taken together suggest that there is still an opportunity to explore ER signaling as potential target domain for future pancreatic cancer therapy.