Novel roles of prolactin and estrogens in breast cancer: resistance to chemotherapy

Abstract

Resistance to chemotherapy is a major complication in the treatment of advanced breast cancer. Estrogens and prolactin (PRL) are implicated in the pathogenesis of breast cancer but their roles in chemoresistance have been overlooked. A common feature to the two hormones is activation of their receptors by diverse compounds, which mimic or antagonize their actions. The PRL receptor is activated by lactogens (PRL, GH, or placental lactogen) originating from the pituitary, breast, adipose tissue, or the placenta. Estrogen receptors exist in multiple membrane-associated and cytoplasmic forms that can be activated by endogenous estrogens, man-made chemicals, and phytoestrogens. Here, we review evidence that low doses of PRL, estradiol (E 2 ), and bisphenol A (BPA) antagonize multiple anticancer drugs that induce cell death by different mechanisms. Focusing on cisplatin, a DNA-damaging drug which is effective in the treatment of many cancer types but not breast cancer, we compare the abilities of PRL, E 2 , and BPA to antagonize its cytotoxicity. Whereas PRL acts by activating the glutathione-S-transferase detoxification enzyme, E 2 and BPA act by inducing the antiapoptotic protein Bcl-2. The implications of these findings to patients undergoing chemotherapy are discussed.

Morphological Changes of Cisplatin-resistant Human Breast Cancer MCF-7 Cell Line

“…In agreement with the results in this study, some reports have suggested that cisplatin resistance on MCF-7 involves antiapoptotic mechanisms, demonstrated by a decrease of DNA-damage effector proteins, which is strongly related to the ability of the resistant cells to tolerate and repair the DNA damage due to cisplatin activity. 5,6,18 In this present study, we demonstrated that in comparison to its parental cell line MCF-7, MCF-7/CisR demonstrated several observable morphological changes. Parental cell line MCF-7 exhibited a regular spindle shape with a smooth cell membrane border, while the resistant cells demonstrated an irregular and spherical shape where some parts or the cell border are unclear (Fig.…”

New concepts in prolactin biology

“…It has been proposed that PRL may promote mammary tumor initiation via the JAK2/STAT5 signaling pathway, but as this cascade also maintains cell differentiation, it may also contribute to suppress invasive characteristics (Nevalainen et al 2004, Wagner & Rui 2008, Tran et al 2010. Otherwise, the concept is emerging that PRL could favor cell motility and confer resistance to chemotherapy, and thereby contribute to metastasis dissemination (for reviews Clevenger et al (2003) and Lapensee & Ben Jonathan (2010)). Such diverse effects may be mediated by distinct signaling cascades.…”

Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice

“…Since incurable cancer, which afflicts over 450 persons per 100,000 annually, is a growing health epidemic, it is important to establish a relationship between environmental xenogens (i.e., endocrine disruptors) and cancer (30). Indeed, recent studies on this subject indicate a growing correlation between high exposure to endocrine disruptors (e.g., bisphenol A, xenoestrogens, polycyclic aromatic hydrocarbons) and cancer risk or drug response (13,(31)(32)(33)(34)(35)(36)(37). The question is particularly relevant given that recent developments in cancer drug therapy (e.g., targeted therapy) are markedly improving survivability.…”

“…Simultaneously, over the last several decades, our burden of environmental xenotoxins has increased substantially. Recent work implicates several xenogens in cancer cell growth and drug resistance (13,(31)(32)(33)(34)(35)(36)(37). Indeed, the molecular pathways governing the tissue-specific phenotypes mediated by chronic exposure to endocrine disruptors are varied, and it is clear that some important effects are mediated via nuclear receptors.…”