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Breast cancer is the second leading cause of cancer-related deaths in women and triple-negative breast cancer (TNBC), in particular, is an aggressive and highly metastatic type of breast cancer that does not respond to established targeted therapies and is associated with poor prognosis and worse survival. Previous studies identified a subgroup of triple-negative breast cancer patients with high expression of estrogen related receptor alpha (ERRα) that has better prognosis when treated with tamoxifen. We therefore set out to identify common targets of tamoxifen and ERRα in the context of TNBC using phosphoproteomic analysis. In this study, we discovered that phosphorylation of mitogen-activated protein kinase 1 (MAPK1) is regulated by tamoxifen as well as ERRα. Additionally, we showed that inhibition of MAPK signaling together with the use of a selective ERRα inverse agonist, XCT-790, leads to a significant upregulation of apoptosis and paves way for the therapeutic use of MAPK inhibitors for treatment of ERRα expressing TNBC.

Lymphangioleiomyomatosis (LAM) is a rare neoplastic metastatic disease affecting women of childbearing age. LAM is caused by hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) as a consequence of tuberous sclerosis complex (TSC) 1/2 inactivation. Clinically, LAM results in cystic lung destruction. mTORC1 inhibition using rapamycin analogs (rapalogs) is partially effective in reducing disease progression and improving lung function. However, cessation of treatment results in continued progression of the disease. In the present study, we investigated the effectiveness of the combination of rapamycin treatment with resveratrol, an autophagy inhibitor, in the TSC2-null xenograft tumor model. We determined that this combination inhibits phosphatidylinositol-4,5-bisphosphate 3-kinase PI3K/Akt/mTORC1 signaling and activates apoptosis. Therefore, the combination of rapamycin and resveratrol may be an effective clinical strategy for treatment of LAM and other diseases with mTORC1 hyperactivation.

Breast cancer is the second leading cause of cancer-related deaths in women and triple-negative breast cancer (TNBC), in particular, is an aggressive and highly metastatic type of breast cancer that does not respond to established targeted therapies and is associated with poor prognosis and worse survival. Previous studies identified a subgroup of triple-negative breast cancer patients with high expression of estrogen related receptor alpha (ERR[alpha]) that has better prognosis when treated with tamoxifen. We therefore set out to identify common targets of tamoxifen and ERR[alpha] in the context of TNBC using phosphoproteomic analysis. In this study, we discovered that phosphorylation of mitogen-activated protein kinase 1 (MAPK1) is regulated by tamoxifen as well as ERR[alpha]. Additionally, we showed that inhibition of MAPK signaling together with the use of a selective ERR[alpha] inverse agonist, XCT-790, leads to a significant upregulation of apoptosis and paves way for the therapeutic use of MAPK inhibitors for treatment of ERR[alpha] expressing TNBC.

PurposeDeregulated PI3K/mTOR signals can promote the growth of breast cancer and contribute to endocrine treatment resistance. This report aims to investigate raptor and its intracellular localization to further understand its role in ER-positive breast cancer.MethodsRaptor protein expression was evaluated by immunohistochemistry in 756 primary breast tumors from postmenopausal patients randomized to tamoxifen or no tamoxifen. In vitro, the MCF7 breast cancer cell line and tamoxifen-resistant MCF7 cells were studied to track the raptor signaling changes upon resistance, and raptor localization in ERα-positive cell lines was compared with that in ERα-negative cell lines.ResultsRaptor protein expression in the nucleus was high in ER/PgR-positive and HER2-negative tumors with low grade, features associated with the luminal A subtype. Presence of raptor in the nucleus was connected with ERα signaling, here shown by a coupled increase of ERα phosphorylation at S167 and S305 with accumulation of nuclear raptor. In addition, the expression of ERα-activated gene products correlated with nuclear raptor. Similarly, in vitro we observed raptor in the nucleus of ERα-positive, but not of ER-negative cells. Interestingly, raptor localized to the nucleus could still be seen in tamoxifen-resistant MCF7 cells. The clinical benefit from tamoxifen was inversely associated with an increase of nuclear raptor. High cytoplasmic raptor expression indicated worse prognosis on long-term follow-up.ConclusionWe present a connection between raptor localization to the nucleus and ERα-positive breast cancer, suggesting raptor as a player in stimulating the growth of the luminal A subtype and a possible target along with endocrine treatment.

Estrogen-related receptor alpha (ERRα) is an orphan nuclear factor that is a master regulator of cellular energy metabolism. ERRα is overexpressed in a variety of tumors, including ovarian, prostate, colorectal, cervical and breast, and is associated with a more aggressive tumor and a worse outcome. In breast cancer, specifically, high ERRα expression is associated with an increased rate of recurrence and a poor prognosis. Because of the common functions of ERRα and the mTORC1/S6K1 signaling pathway in regulation of cellular metabolism and breast cancer pathogenesis, we focused on investigating the biochemical relationship between ERRα and S6K1. We found that ERRα negatively regulates S6K1 expression by directly binding to its promoter. Downregulation of ERRα expression sensitized ERα-negative breast cancer cells to mTORC1/S6K1 inhibitors. Therefore, our results show that combinatorial inhibition of ERRα and mTORC1/S6K1 may have clinical utility in treatment of triple-negative breast cancer, and warrants further investigation. Cancer: Dual drug strategy for breast tumors Targeting a protein linked to poor prognosis in breast cancer patients could help sensitize tumors to other drug therapies. A US team led by Marina Holz of Yeshiva University, New York, investigated the biochemical relationship between estrogen-related receptor alpha (ERRa) and the 40S ribosomal S6 kinase 1 (S6K1), both of which serve common functions in controlling cellular growth, proliferation and metabolism. Working with breast cancer cells in a lab dish and mouse models, they showed that ERRa binds the promoter of the gene encoding S6K1, leading to reduced gene expression. Blocking ERRa activity led to higher levels of S6K1, and these S6K1-expressing breast cancer cells were more susceptible to anti-S6K1 drugs and other agents in the same pathway. The researchers suggest that combined inhibition of ERRa and S6K1 could have therapeutic potential.

Estrogen-related receptor alpha (ERRα) is an orphan nuclear factor that is a master regulator of cellular energy metabolism. ERRα is overexpressed in a variety of tumors, including ovarian, prostate, colorectal, cervical and breast, and is associated with a more aggressive tumor and a worse outcome. In breast cancer, specifically, high ERRα expression is associated with an increased rate of recurrence and a poor prognosis. Because of the common functions of ERRα and the mTORC1/S6K1 signaling pathway in regulation of cellular metabolism and breast cancer pathogenesis, we focused on investigating the biochemical relationship between ERRα and S6K1. We found that ERRα negatively regulates S6K1 expression by directly binding to its promoter. Downregulation of ERRα expression sensitized ERα-negative breast cancer cells to mTORC1/S6K1 inhibitors. Therefore, our results show that combinatorial inhibition of ERRα and mTORC1/S6K1 may have clinical utility in treatment of triple-negative breast cancer, and warrants further investigation.