**2. The role of sex steroid hormone receptors in cancer therapy**

The function of sex steroid hormone receptors in breast cancer has been extensively studied and the findings applied to diagnosis and treatment (Clarke & Sutherland, 1990; Kester et al., 1997) Estrogen stimulates cell proliferation of breast epithelial cells, and the close relationship between the expression of estrogen receptor (ER) and the prognosis of breast cancer has been well characterized (Ma et al., 2009). Progesterone levels fluctuate during the menstrual cycle and regulate cell proliferation and differentiation; however, less is known regarding its role in breast cancer (Jeng et al., 1992; Sutherland et al., 1988; van der Burg et al., 1992) We have previously reported that introducing progesterone receptor (PR) into hormone-independent breast cancer cells significantly suppresses their proliferative and invasive activities upon progesterone treatment (Sumida et al., 2004). Several drugs, such as

Hormone Therapy for the Treatment of Patients with Malignant Salivary Gland Tumor (MSGT) 317

**3. Pathological and biological similarities between MSGTs and breast cancer**  Mammary and salivary glands are tubulo-acinar exocrine glands that share similar morphological characteristics. Similar histological features are observed when the tumors arising from these 2 sites are compared (Camelo-Piragua et al., 2009; Hellquist et al., 1994; Marchio et al., 2010; Pia-Foschini et al., 2003). Although the cancers differ in terms of their incidence and clinical behavior, certain biological features have been described in both entities and potential common therapeutic approaches have been considered. The WHO classification of MSGTs lists more than 20 different histological subtypes (Laurie et al., 2006; Milano et al., 2007). The majority of these are divided into 2 groups—those of secretory duct origin (including mucoepidermoid carcinoma [MEC] and salivary duct carcinoma [SDC]) and those of intercalated origin (including adenoid cystic carcinoma [ACC]) (Batsakis et al., 1989; Dardick et al., 1987). Most of these tumors occur in the parotid gland (70%), and less than 25% are malignant (Glisson et al., 2004). Although the incidence of tumors at other sites such as the submandibular, sublingual, and minor salivary glands is less common, malignancy at these sites is higher, approximating 50% (Glisson et al., 2004). Most aggressive breast cancers are composed of invasive ductal carcinomas, and other histologic features such as MEC and ACC are relatively rare. Below, we briefly describe some of the types of MSGTs that display features (at the morphological and molecular level) that they have in common with breast cancers, and could therefore provide potential common

MEC is the most common salivary gland neoplasm, accounting for 29–34% of all malignancies of the major and minor salivary glands (Milano et al., 2007). These tumors grow slowly and present as painless masses in most cases. They are primarily composed of intermediate, mucous, and epidermoid cells. The cell types are classified histologically as low-, intermediate-, and high-grade; 5-year overall survival (OS) varies from 92% to 100% for low-grade tumors, 62% to 92% for intermediate-grade tumors, and 0% to 43% for highgrade tumors (Pires et al., 2004). High-grade MEC is an aggressive malignancy, characterized by high rates of local recurrence and distant metastasis. On the contrary, lowgrade MECs generally do not metastasize. MEC of the breast is a rare entity with an estimated incidence of 0.2% and is composed of a mixture of basaloid, intermediate, epidermoid, and mucinous cells (Camelo-Piragua et al., 2009; Fisher et al., 1983). Since Patchefsky et al. first described breast MEC in 1979, only 28 cases have been reported (Berry et al., 1998; Chang et al., 1998; Di Tommaso et al., 2004; Fisher et al., 1983; Gomez-Aracil et al., 2006; Hanna et al., 1985; Hastrup et al., 1985; Hornychova et al., 2007; Kovi et al., 1981; Leong et al., 1985; Luchtrath et al., 1989; Markopoulos et al., 1998; Patchefsky et al., 1979; Pettinato et al., 1989; Ratanarapee et al., 1983; Tjalma et al., 2002). Because of its rarity, the prognosis remains controversial debatable matter. However, MECs from the breasts and salivary glands have been shown to share similar biological features and morphologies (Camelo-Piragua et al., 2009). Researchers have classified breast MECs into 3 grades by using the same grading system as for salivary gland tumors and have demonstrated that high-grade tumors are associated with high mortality as a result of lymph node and distant metastases. These results suggest that MECs from both mammary and salivary glands have similar morphological features, and thus could have similar treatment strategies. Further, a common cytogenetic alteration of breast and salivary MECs has been reported. A reciprocal

therapeutic strategies.

**3.1 Mucoepidermoid carcinoma (MEC)** 

Tamoxifen, an estrogen receptor antagonist, and a synthetic progestin similar to progesterone, are considered to be effective at inhibiting tumor cell proliferation. These drugs are given as adjuvant therapies to breast cancer patients when immunohistochemical staining of their tumor tissue indicates that >10% of the breast cancer cells express ER or PR (Horwitz, 1993; Williams et al., 2007). Molecular-targeted drug therapy is generally less toxic than traditional chemotherapy; however, some studies have reported severe side effects, and carefully designed and regulated clinical trials are necessary to confirm their safety. Moreover, these types of therapies are not viable when a tumor expresses a low level of a molecular target such as a receptor (Ismail-Khanet al., 2010). This problem is exemplified by breast cancers that do not express ER, PR, or HER2 receptors, that is, in triple negative cases. It is a challenge for clinicians to provide efficacious treatments for this patient population.

Sex steroid hormone therapy in prostate cancers is based on their high sensitivity to androgen inhibition. The most common hormone therapy is initiated by reducing the concentration of circulating androgens through surgical or medical castration and/or by administering anti-androgens such as flutamide or bicalutamide (Klotz et al., 2005; Miyake et al., 2005). However, in almost all patients, the efficacy of the treatment decreases over time as the tumor becomes "androgen-refractory" (Yuan et al., 2009). As a result, these patients develop distant metastases, such as in the bone, which eventually proves fatal to the patient. Therefore, the molecular events that control the transition from androgen-sensitive prostate cancer to androgen-refractory prostate cancer need to be elucidated.

Accumulating evidence suggests that the androgen receptor (AR) plays a critical role in regulating the growth of both androgen-sensitive and androgen-refractory prostate cancer (Chen et al., 2004; Debes et al., 2004; Grossmann et al., 2001; Hara et al., 2003; Scher et al., 2005; Taplin et al., 2004). In addition, recent studies have shown that the AR can regulate invasion and metastasis (Hara et al., 2008). In AR-negative cell lines such as PC3 and DU145, it has been shown that forced AR expression decreases their invasive properties and treatment with androgen further reduces invasion by these cells (Bonaccorsi et al., 2000; Cinar et al., 2001). Moreover, it has been reported that hormone-refractory prostate cancers have a variety of AR alterations that are either not found in hormone-naive tumors or are found at a lower frequency (Taplin et al., 2004). A more recent investigation demonstrated that forced expression of AR in a subline of a metastatic androgen-dependent prostate cancer cell line led to increased invasion (Hara et al., 2008). It is clear that a more detailed understanding of the AR alterations in the evolution of androgen-refractory prostate cancer is needed to help drive the development of potential new therapies.

Few studies of ovarian and colon cancer have addressed the potential application of hormone therapies (Burkman, 2002). In ovarian cancer, the use of estrogen as a menopausal therapy has frequently been associated with an increased risk of ovarian cancer, and there is still conflicting evidence regarding the impact of hormone therapy in terms of decreasing the risk of cancer (Greiser et al., 2010). A recent study, however, suggested that this problem can be circumvented by co-administering progestin and estrogen (Pearce et al., 2009). Further, experiments in culture showed that progesterone reduced the proliferation of both benign and malignant ovarian tumor cells (Zhou et al., 2002). Therefore, progestin might be a key factor for preventing and suppressing ovarian cancer cell growth. In contrast to ovarian cancer, estrogen appears to have protective effects against colon cancer (Kennelly et al., 2008). However, the role of hormone replacement therapy with estrogen for the treatment of colon cancer is poorly understood, and further analyses are needed.
