**4. Hormone therapy for the treatment of patients with MSGTs**

As described above, several types of MSGTs are morphologically and biologically similar to malignant breast cancers (Pia-Foschini et al., 2003; Wick et al., 1998) (Fig. 1). Further, the clinical significance of sex hormone receptors has been debated since White and Garcelon first described therapy with estrogen against salivary gland neoplasms in 1955 (White & Garcelon, 1955). Previous reports obtained using a low number of biopsy samples have shown conflicting results regarding the expression of sex hormone receptors, making it difficult to determine the potential benefits of hormone therapy (Barnes et al., 1994; Barrera et al., 2008; Dimery et al., 1987; Dori et al., 2000; Jeannon et al., 1999; Lamey et al., 1987; Lewis et al., 1996; Miller et al., 1994; Nasser et al., 2003; Pires et al., 2004; Shick et al., 1995). Therefore, additional studies are required in order to clarify the role of hormone receptors in MSGTs. Although several studies have examined ER and PR expression in MSGTs, there is substantial disparity in the results: the expression of ER and PR varies from 0 to 86% and 0 to 50%, respectively (Barnes et al., 1994; Barrera et al., 2008; Dimery et al., 1987; Dori et al., 2000; Jeannon et al., 1999; Lamey et al., 1987; Lewis et al., 1996; Miller et al., 1994; Nasser et

Hormone Therapy for the Treatment of Patients with Malignant Salivary Gland Tumor (MSGT) 321

Williams et al. reported that most tumors derived from breast and salivary glands expressed estrogen receptor-beta (ER-β) and that the patients whose tumors lacked ER-β were at higher risk for local recurrence (Williams et al., 2007). In addition, previous studies have linked the loss of ER expression to aggressive features in adenocarcinomas of the breast, prostate, and colon (Foley et al., 2000; Fuqua et al., 2003; Leygue et al., 1999; Maggiolini et al., 2004; Strom et al., 2004; Wong et al., 2005). In breast and prostate carcinoma, ER-β has been shown to inhibit cell proliferation via the cyclin D1 pathway, and to induce apoptosis by downregulating bcl-2 and/or by inducing Bax expression (Bardin et al., 2004; Pettersson et al., 2000). Targeting ER-β may therefore become a useful approach for the management of salivary duct carcinoma. In our previous studies, we determined that MSGT cell lines in culture lacked estrogen and progesterone receptors. However, the lack of hormone receptors may be a consequence of malignant transformation and may represent a requirement for the establishment of immortal cell lines. Other clinical studies have reported the efficacy of Tamoxifen against MSGTs (Elkin & Jacobs, 2008; Shadaba et al., 1997), and one resulted in long-term survival even though in these patients, no ER was detected by immunohistochemistry. This result appears to be supported by another case report where Tamoxifen could reactivate ER expression (Sharma et al., 2006). Our previous studies showed that progesterone could suppress MGST cell aggressiveness in a manner similar to that observed in breast cancer cells (Fig. 2). Specifically, we demonstrated that after transduction of PR, progesterone could significantly suppress the proliferation (and invasion) of MSGT cells (Yoshimura et al., 2007). This suppression did not lead to cell death, but instead to cell cycle arrest. These data suggest that if MSGTs express significant levels of PR, then progesterone treatment may slow the growth of the primary tumor and potentially shift it to a dormant state. Since most MSGTs occur in elderly patients, triggering tumor dormancy could improve the quality of

Fig. 2. Pg suppresses proliferation and invasion of both salivary gland and breast cancer

cells.

al., 2003; Pires et al., 2004; Shick et al., 1995). These disparities may be explained by differences in the antibodies used, the experimental methods of detection (e.g., Western blotting vs. immunohistochemistry), and the criteria used for ruling out false positives and negatives. It is therefore particularly critical to standardize protocols in a way similar to that described for the analysis of breast cancer tissues. Some of the differences might also result from an insufficient number of samples.

X 200

Salivary glands and mammary glands are both tubulo-acinar exocrine tissues sharing similar morphological features. It is therefore expected that the tumors originating from these two different glands would show similarities in their response to hormonal treatment.

Fig. 1. Histological comparison of malignant salivary and mammary gland tumors.

Even though ER expression is unlikely to represent a useful marker for detecting MSGTs, a subset of MSGTs clearly expresses hormone receptors, and these receptors could control disease progression. Thus, current therapeutic strategies in breast cancer patients may also be effective for the treatment of MSGTs. Moreover, the feasibility of hormone therapy seems to be supported by accumulating reports of AR expression in SDCs. Although the expression of AR is generally rare in salivary gland neoplasms, SDCs commonly express AR in 92–100% of cases (Fan et al., 2001; Kapadia et al., 1998; Moriki et al., 2001). Recently, Jaspers et al. reported that androgen deprivation therapy (ADT) in patients with recurrent or disseminated disease showed a clinical benefit in 5 out of 10 cases, and 2 of these had partial responses (Jaspers et al., 2011). This approach is therefore more effective than the results obtained with chemotherapy. Given the fact that ADT generally has less adverse effects than chemotherapy, anti-androgen therapy may lead to better clinical outcomes and could become a standard treatment for SDCs.

al., 2003; Pires et al., 2004; Shick et al., 1995). These disparities may be explained by differences in the antibodies used, the experimental methods of detection (e.g., Western blotting vs. immunohistochemistry), and the criteria used for ruling out false positives and negatives. It is therefore particularly critical to standardize protocols in a way similar to that described for the analysis of breast cancer tissues. Some of the differences might also result

Salivary glands and mammary glands are both tubulo-acinar exocrine tissues sharing similar morphological features. It is therefore expected that the tumors originating from these two different

Fig. 1. Histological comparison of malignant salivary and mammary gland tumors.

Even though ER expression is unlikely to represent a useful marker for detecting MSGTs, a subset of MSGTs clearly expresses hormone receptors, and these receptors could control disease progression. Thus, current therapeutic strategies in breast cancer patients may also be effective for the treatment of MSGTs. Moreover, the feasibility of hormone therapy seems to be supported by accumulating reports of AR expression in SDCs. Although the expression of AR is generally rare in salivary gland neoplasms, SDCs commonly express AR in 92–100% of cases (Fan et al., 2001; Kapadia et al., 1998; Moriki et al., 2001). Recently, Jaspers et al. reported that androgen deprivation therapy (ADT) in patients with recurrent or disseminated disease showed a clinical benefit in 5 out of 10 cases, and 2 of these had partial responses (Jaspers et al., 2011). This approach is therefore more effective than the results obtained with chemotherapy. Given the fact that ADT generally has less adverse effects than chemotherapy, anti-androgen therapy may lead to better clinical outcomes and

glands would show similarities in their response to hormonal treatment.

could become a standard treatment for SDCs.

Adenoid Cystic Carcinoma Ductal Carcinoma

X 200

from an insufficient number of samples.

Malignant Salivary Gland Tumor

Breast Cancer

Williams et al. reported that most tumors derived from breast and salivary glands expressed estrogen receptor-beta (ER-β) and that the patients whose tumors lacked ER-β were at higher risk for local recurrence (Williams et al., 2007). In addition, previous studies have linked the loss of ER expression to aggressive features in adenocarcinomas of the breast, prostate, and colon (Foley et al., 2000; Fuqua et al., 2003; Leygue et al., 1999; Maggiolini et al., 2004; Strom et al., 2004; Wong et al., 2005). In breast and prostate carcinoma, ER-β has been shown to inhibit cell proliferation via the cyclin D1 pathway, and to induce apoptosis by downregulating bcl-2 and/or by inducing Bax expression (Bardin et al., 2004; Pettersson et al., 2000). Targeting ER-β may therefore become a useful approach for the management of salivary duct carcinoma.

In our previous studies, we determined that MSGT cell lines in culture lacked estrogen and progesterone receptors. However, the lack of hormone receptors may be a consequence of malignant transformation and may represent a requirement for the establishment of immortal cell lines. Other clinical studies have reported the efficacy of Tamoxifen against MSGTs (Elkin & Jacobs, 2008; Shadaba et al., 1997), and one resulted in long-term survival even though in these patients, no ER was detected by immunohistochemistry. This result appears to be supported by another case report where Tamoxifen could reactivate ER expression (Sharma et al., 2006). Our previous studies showed that progesterone could suppress MGST cell aggressiveness in a manner similar to that observed in breast cancer cells (Fig. 2). Specifically, we demonstrated that after transduction of PR, progesterone could significantly suppress the proliferation (and invasion) of MSGT cells (Yoshimura et al., 2007). This suppression did not lead to cell death, but instead to cell cycle arrest. These data suggest that if MSGTs express significant levels of PR, then progesterone treatment may slow the growth of the primary tumor and potentially shift it to a dormant state. Since most MSGTs occur in elderly patients, triggering tumor dormancy could improve the quality of

Fig. 2. Pg suppresses proliferation and invasion of both salivary gland and breast cancer cells.

Hormone Therapy for the Treatment of Patients with Malignant Salivary Gland Tumor (MSGT) 323

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life, and may be a successful way to allow the patient to live a normal lifespan. Although the 5-year OS in patients with MSGTs represents the average, extended survival rates are extremely low (Lones et al., 1997; Lopes et al., 1998; Spiro, 1997). MSGTs show low sensitivity to chemotherapy and surgery because of anatomical limitations (Marabdas et al., 1990; Takagi et al., 2001). Since radiation is also less effective, novel therapeutic approaches are eagerly anticipated. Triggering tumor dormancy as a consequence of hormone therapy could represent a novel strategy for the treatment of patients with MSGTs.

In our recent studies, the inhibitory effect of Pg on the proliferative and invasive activities of the salivary gland and breast tumor cells was demonstrated, suggesting some common mechanisms. In both types of cancers, expression of Id-1 and c-myc was down-regulated after Pg treatment, whereas p21 expression level was up-regulated.

#### **5. Conclusions**

Besides surgical resection and radiation of MSGTs, there are no other effective therapies. Adjuvant therapy is generally reserved for palliative treatment; however, there is no clear evidence that such treatment can bring clinical benefits. Since adverse effects caused by chemotherapy often threaten the life of a patient, and since some patients with specific MSGTs, especially ACCs, show long survival even with multiple metastases, the adoption of adjuvant therapy should be carefully considered. To achieve new therapeutic methods, it is now necessary to clarify several unanswered questions regarding the expression and/or function of sex steroid hormone receptors in MSGTs. As indicated by AR expression in SDCs, there is now evidence linking hormone receptors and growth factor receptors to the disease. Expression of these receptors could render tumors sensitive to hormone therapy. However, to improve clinical outcomes of patients with rather rare malignancies, more accurate data obtained from multiple and larger studies are required. MSGTs tend to occur in elderly patients, and triggering tumor dormancy could be a successful means of slowing disease progression, therefore providing an improvement in their quality of life. Our studies on PR-negative cells also suggest that induction of hormone receptor gene expression might be an option for delaying disease progression. Based on multiple lines of evidence from a range of cancers, sex steroid hormone receptors may prove to be appropriate targets for the establishment of novel treatments for patients with MSGTs.

#### **6. References**


life, and may be a successful way to allow the patient to live a normal lifespan. Although the 5-year OS in patients with MSGTs represents the average, extended survival rates are extremely low (Lones et al., 1997; Lopes et al., 1998; Spiro, 1997). MSGTs show low sensitivity to chemotherapy and surgery because of anatomical limitations (Marabdas et al., 1990; Takagi et al., 2001). Since radiation is also less effective, novel therapeutic approaches are eagerly anticipated. Triggering tumor dormancy as a consequence of hormone therapy

In our recent studies, the inhibitory effect of Pg on the proliferative and invasive activities of the salivary gland and breast tumor cells was demonstrated, suggesting some common mechanisms. In both types of cancers, expression of Id-1 and c-myc was down-regulated

Besides surgical resection and radiation of MSGTs, there are no other effective therapies. Adjuvant therapy is generally reserved for palliative treatment; however, there is no clear evidence that such treatment can bring clinical benefits. Since adverse effects caused by chemotherapy often threaten the life of a patient, and since some patients with specific MSGTs, especially ACCs, show long survival even with multiple metastases, the adoption of adjuvant therapy should be carefully considered. To achieve new therapeutic methods, it is now necessary to clarify several unanswered questions regarding the expression and/or function of sex steroid hormone receptors in MSGTs. As indicated by AR expression in SDCs, there is now evidence linking hormone receptors and growth factor receptors to the disease. Expression of these receptors could render tumors sensitive to hormone therapy. However, to improve clinical outcomes of patients with rather rare malignancies, more accurate data obtained from multiple and larger studies are required. MSGTs tend to occur in elderly patients, and triggering tumor dormancy could be a successful means of slowing disease progression, therefore providing an improvement in their quality of life. Our studies on PR-negative cells also suggest that induction of hormone receptor gene expression might be an option for delaying disease progression. Based on multiple lines of evidence from a range of cancers, sex steroid hormone receptors may prove to be appropriate targets for the

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**5. Conclusions** 

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