br Introduction Mammary gland development is controlled
Introduction Mammary gland development is controlled by the endocrine system, in particular by the ovarian steroid hormones, estrogen and progesterone, and by the pituitary hormones, growth hormone (GH) and prolactin. Studies in animal models showed that GH deficiency impairs mammary gland development. Spontaneous dwarf rats, which bear a loss-of-function mutation in GH, have deficient alveolar development that can be rescued by GH reinfusion (Swanson and Unterman, 2002). Ghr knockout (KO) mice have retarded duct development and limited side branching (Bocchinfuso and Korach, 1997; Zhou et al., 1997). In humans, mutations affecting the expression and function of the GH receptor (GHR) are collectively known as Laron syndrome (LS). Similar to Ghr KO mice, these patients have short stature and reduced body weight (Laron and Klinger, 1994). Mammary gland development is affected but can support normal lactation. Sustained exposure to steroid hormones constitutes one of the best established factors of risk for breast cancer (Russo and Russo, 2006). There is compelling evidence, from both animal work and epidemiological studies, that elevated levels of GH also increase the risk of breast cancer (De Stavola et al., 2004; Gunnell et al., 2001). The incidence of cancers is higher in patients with acromegaly, a condition associated with hypersecretion of GH (Jenkins, 2004; Perry et al., 2008; van Garderen and Schalken, 2002; Waters and Barclay, 2007), and in individuals with taller height (Ahlgren et al., 2004; Green et al., 2011; De Stavola et al., 2004; Gunnell et al., 2001). Conversely, no cancers have been diagnosed so far in patients with LS (two cohorts studied, of 169 and 230 patients), although they have a higher longevity than the general population (Laron, 2008). Their blood relatives had an incidence of cancers of 24%. There is evidence that GH can be secreted by breast cancer straight from the source (Chiesa et al., 2011; Raccurt et al., 2002). Studies from Lobie’s group have reported that autocrine GH signaling in MCF7 cells confers a mesenchymal, invasive phenotype in vitro and generates more aggressive tumors in vivo (Mukhina et al., 2004). Although the molecular mechanisms underlying steroid hormones and GH signaling have been elucidated in studies spanning decades of research, it is still poorly understood how exposure to these hormones increases risk of breast cancer.
Discussion Initially, the role of GH in both normal breast development and tumorigenesis was linked to that of prolactin, because human GH activates both GHR and prolactin receptor. Subsequently, its role in insulin growth factor-1 (IGF-1) synthesis by the liver and the importance of the GH/IGF-1 axis in cancer initiation and progression were brought to the foreground (Kleinberg et al., 2009; Laban et al., 2003). More recently, a novel hypothesis was proposed, that autocrine/paracrine mechanisms employing locally secreted GH may promote growth in certain tumors, independent of IGF-1 signaling (Mukhina et al., 2004; Zhu et al., 2005). It has been also speculated that the association between GH and cancer risk is due to an effect on the stem/progenitor cell population (Green et al., 2011). We also showed that GH can be secreted locally in the mammary gland, by a population of cells situated in proximity of PR+ cells. Treatment with progestins increased GH mRNA and protein levels in normal breast epithelial cells. Indirect evidence for a link between GH secretion and progesterone also comes from studies in human patients in which serum peaks of GH correlate with those of progesterone in 24 hr cycles or during the lutheal phase of the menstrual cycle (Caufriez et al., 2009, 2011). Signaling through ER and PR is critical for mammary morphogenesis (Bocchinfuso and Korach, 1997; Sternlicht, 2006). Mouse mammary stem cells do not express ER or PR but respond to progesterone stimulation through indirect mechanisms, involving RANK-L, amphiregulin, and Wnt (Asselin-Labat et al., 2010; Beleut et al., 2010; Brisken et al., 2000; Joshi et al., 2010). There is evidence that human mammary stem/progenitor cells are ER−/PR− as well (Honeth et al., 2014; Lim et al., 2009). ALDH1A1+ cells and mammosphere-initiating cells of human origin, are also ER−, but can generate ER+/PR+ cells (Honeth et al., 2014). We showed here that treatment with progestins increased mammosphere formation through paracrine mechanisms mediated by GH. GHA treatment and GHR kd abolished this effect. We propose that part of the communication between PR+ mammary epithelial cells and GHR+ progenitor cells is mediated by GH.