Estrogen therapy (ET) is most effective to reduce menopausal symptoms and prevent other disorders associated with estrogen deficiency. However, Women's Health Initiative studies found that hormone therapy (HT) containing estrogen plus progestogen, but not estrogen-alone increases breast cancer (BC) risk. To prevent the increase in BC risk and yet relieve menopausal symptoms, a novel HT with 17β-estradiol (E2) for symptom relief, progesterone (P4) for uterine protection and melatonin (Mel) for both BC and uterine protection was designed. Inclusion of Mel was postulated to offer uterine protection with lower P4 dose and protect against BC. The goal of this study was to assess the efficacy of E2, P4 and Mel Therapy (EPMT) on mammary cancer (MC) and uterine protection in MMTV-Neu mouse model that mimics HER2 BC. Starting at 2 months age, female mice received Mel in drinking water at night to supplement endogenous Mel surge; while E2 and P4 Therapy (EPT) was provided continuously in diet until 14 months with weekly MC onset and growth monitoring. Normal mammary, uterus and mammary tumors harvested by month 14 were analyzed for potential mechanisms. The results from this study revealed that EPMT delayed tumor onset leading to a decrease in MC incidence. In addition, mice in the EPMT group had no increase in relative uterine weight as opposite to an increase of this parameter in EPT group versus control. The percent tumor-bearing mice with gross metastatic lung lesions were reduced in Mel, EPT and EPMT groups. Mel receptor, estrogen receptor (ER) and progesterone receptor (PR) expression revealed that all tissues examined have Mel receptors. However, ER and PR expression varied. In normal mammary tissue, both ERα and PR were detected by immunohistochemistry. However, no ERα and PR were detected in mammary tumors of same mice. In uterus, mice given Mel or EPMT had significant decreases in PR expression but no change in ERα expression compared to control suggesting that Mel-mediated inhibition of ER binding to estrogen response elements may be involved in the down regulation of uterine PRs. Overall, this study reveal that EPMT prevents mammary cancer and may protect against uterotrophy. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences; / Pharmacology / PhD; / Dissertation;

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Estrogen therapy (ET) is most effective to reduce menopausal symptoms and prevent other disorders associated with estrogen deficiency. However, Women's Health Initiative studies found that hormone therapy (HT) containing estrogen plus progestogen, but not estrogen-alone increases breast cancer (BC) risk. To prevent the increase in BC risk and yet relieve menopausal symptoms, a novel HT with 17β-estradiol (E2) for symptom relief, progesterone (P4) for uterine protection and melatonin (Mel) for both BC and uterine protection was designed. Inclusion of Mel was postulated to offer uterine protection with lower P4 dose and protect against BC. The goal of this study was to assess the efficacy of E2, P4 and Mel Therapy (EPMT) on mammary cancer (MC) and uterine protection in MMTV-Neu mouse model that mimics HER2 BC. Starting at 2 months age, female mice received Mel in drinking water at night to supplement endogenous Mel surge; while E2 and P4 Therapy (EPT) was provided continuously in diet until 14 months with weekly MC onset and growth monitoring. Normal mammary, uterus and mammary tumors harvested by month 14 were analyzed for potential mechanisms. The results from this study revealed that EPMT delayed tumor onset leading to a decrease in MC incidence. In addition, mice in the EPMT group had no increase in relative uterine weight as opposite to an increase of this parameter in EPT group versus control. The percent tumor-bearing mice with gross metastatic lung lesions were reduced in Mel, EPT and EPMT groups. Mel receptor, estrogen receptor (ER) and progesterone receptor (PR) expression revealed that all tissues examined have Mel receptors. However, ER and PR expression varied. In normal mammary tissue, both ERα and PR were detected by immunohistochemistry. However, no ERα and PR were detected in mammary tumors of same mice. In uterus, mice given Mel or EPMT had significant decreases in PR expression but no change in ERα expression compared to control suggesting that Mel-mediated inhibition of ER binding to estrogen response elements may be involved in the down regulation of uterine PRs. Overall, this study reveal that EPMT prevents mammary cancer and may protect against uterotrophy. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences; / Pharmacology / PhD; / Dissertation;

<p>Breast cancer is the most common cancer among Canadian women with one in nine women expected to develop breast cancer in their lifetime. Until recently these breast tumors were thought to be a homogeneous cell population. Recent studies have shown that breast tumors contain a rare cell type termed breast tumor initiating cells (TICs) or cancer stem cells (CSCs) with the ability to elicit new tumor growth and metastases. These TICs exist apex of a tumor cell hierarchy and give rise to more TICs and non-tumorigenic cells. Traditionally, drugs were developed to target the highly proliferative cells population resulting in a decrease in tumor volume. However, these therapies spare the TICs, which results in tumor relapse demonstrating the need for new drugs that target the TICs. Because in cancer, mutated protein kinases are the controllers of cell proliferation, invasion and metastasis, they have become a target for drug development. Inhibition of these kinases could lead to the identification of compounds that selectively target breast TICs. Using mammary tumors from cancer prone mice propagated as non-adherent tumorspheres (TMS), which contain a high fraction of breast TICs and the same conditions to propagate the non-transformed mouse mammary epithelial stem and progenitor cells (MESC), as non-adherent mammospheres (MMS) a 240-kinase inhibitor library was screened using an AlamarBlue proliferation assay. Twenty percent of the compounds resulted in 75% decrease in proliferation of TMS derived cells and some of which were TMS-selective. Sunitinib, a multi-targeted kinase inhibitor, was one of the selective compounds identified and when administered to mice with subcutaneous mammary tumors resulted in tumor shrinkage. This was accompanied by an increase in apoptotic cells, decrease in proliferating cells and tumor vasculature, and a change in tumor morphology and composition. These findings show the efficacy of Sunitinib in shrinking mouse mammary tumors and suggest a potential use of Sunitinib for treatment of breast cancer.</p> / Master of Science (MSc)