Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase

Brown, Kristy A.; Hunger, Nicole I.; Docanto, Maria; Simpson, Evan R.

doi:10.1007/s10549-010-0834-y

Cited by 123 publications

(102 citation statements)

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“…In addition, its expression is regulated by oncogenes such as HER-2/neu and tumor suppressor genes including BRCA1, LKB1, and p53 (9,11,(13)(14)(15)(16)(17)(18). Germ line mutations in the TP53 gene, which encodes p53, lead to Li-Fraumeni Syndrome (LFS).…”

mentioning

confidence: 99%

Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells

Subbaramaiah

Brown

Zahid

et al. 2016

Journal of Biological Chemistry

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Li-Fraumeni syndrome (LFS) patients harbor germ line mutations in the TP53 gene and are at increased risk of hormone receptor-positive breast cancers. Recently, elevated levels of aromatase, the rate-limiting enzyme for estrogen biosynthesis, were found in the breast tissue of LFS patients. Although p53 down-regulates aromatase expression, the underlying mechanisms are incompletely understood. In the present study, we found that LFS stromal cells expressed higher levels of Hsp90 ATPase activity and aromatase compared with wild-type stromal cells. Inhibition of Hsp90 ATPase suppressed aromatase expression. Silencing Aha1 (activator of Hsp90 ATPase 1), a cochaperone of Hsp90 required for its ATPase activity, led to both inhibition of Hsp90 ATPase activity and reduced aromatase expression. In comparison with wild-type stromal cells, increased levels of the Hsp90 client proteins, HIF-1␣, and PKM2 were found in LFS stromal cells. A complex comprised of HIF-1␣ and PKM2 was recruited to the aromatase promoter II in LFS stromal cells. Silencing either HIF-1␣ or PKM2 suppressed aromatase expression in LFS stromal cells. CP-31398, a p53 rescue compound, suppressed levels of Aha1, Hsp90 ATPase activity, levels of PKM2 and HIF-1␣, and aromatase expression in LFS stromal cells. Consistent with these in vitro findings, levels of Hsp90 ATPase activity, Aha1, HIF-1␣, PKM2, and aromatase were increased in the mammary glands of p53 null versus wild-type mice. PKM2 and HIF-1␣ were shown to co-localize in the nucleus of stromal cells of LFS breast tissue. Taken together, our results show that the Aha1-Hsp90-PKM2/ HIF-1␣ axis mediates the induction of aromatase in LFS.Estrogen is an important mediator in the development and progression of breast cancer. Cytochrome P450 aromatase, a product of the CYP19A1 gene, catalyzes the synthesis of estrogens from androgens (1). In postmenopausal women, the adipose tissue becomes the main site of estrogen biosynthesis, and particularly, the breast adipose tissue is considered an important source of estrogens that drive the growth of hormone-dependent breast cancers. Consequently, it is important to elucidate the mechanisms that regulate the transcription of the CYP19A1 gene. The expression of aromatase is tightly regulated, with transcription being under the control of several distinct tissue-selective promoters (2-4). In normal breast adipose tissue, aromatase is expressed at low levels under the control of promoter I.4, whereas in obesity and cancer, the coordinated activation of the proximal promoters I.3 and promoter II (PII) 3 causes a significant increase in aromatase expression (3-5). The proximal promoters I.3 and PII are located close to each other, activated by stimulation of the cAMP 3 PKA 3 cAMP response element-binding protein (CREB) pathway (6, 7), and aided by many other regulators including CREB-regulated transcription co-activator 2 (CRTC2), p300, and hypoxia-inducible factor-1␣ (HIF-1␣) (8 -11).Several cytokines and tumor promoters, including prostaglandin E 2 , tumor necrosis ...

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confidence: 99%

Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells

Subbaramaiah

Brown

Zahid

et al. 2016

Journal of Biological Chemistry

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“…By contrast, adiponectin, in which levels are inversely proportional to adiposity, stimulates AMPK and, hence, inhibits aromatase expression. Metformin acts in a similar fashion to adiponectin to stimulate AMPK and inhibit aromatase expression, hence, providing one mechanism for the observations that metformin is protective against breast cancer (Brown et al 2010). Thus, we see that AMPK plays a central inhibitory role in the mechanisms whereby inflammation and obesity regulate aromatase expression in the breast.…”

Section: Source Of Oestrogensmentioning

confidence: 77%

Celebrating 75 years of oestradiol

Simpson

Santen

2015

Journal of Molecular Endocrinology

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Oestrogens exert important effects on the reproductive as well as many other organ systems in both men and women. The history of the discovery of oestrogens, the mechanisms of their synthesis, and their therapeutic applications are very important components of the fabric of endocrinology. These aspects provide the rationale for highlighting several key components of this story. Two investigators, Edward Doisy and Alfred Butenandt, purified and crystalized oestrone nearly simultaneously in 1929, and Doisy later discovered oestriol and oestradiol. Butenandt won the Nobel Prize for this work and Doisy's had to await his purification of vitamin K. Early investigators quickly recognized that oestrogens must be synthesized from androgens and later investigators called this process aromatization. The aromatase enzyme was then characterized, its mechanism determined, and its structure identified after successful crystallization. With the development of knock-out methodology, the precise effects of oestrogen in males and females were defined and clinical syndromes of deficiency and excess described. Their discovery ultimately led to the development of oral contraceptives, treatment of menopausal symptoms, therapies for breast cancer, and induction of fertility, among others. The history of the use of oestrogens for postmenopausal women to relieve symptoms has been characterized by cyclic periods of enthusiasm and concern. The individuals involved in these studies, the innovative thinking required, and the detailed understanding made possible by evolving biologic and molecular techniques provide many lessons for current endocrinologists. Discovery of oestrogenThe concept that substances secreted by one organ could then be transported internally to another via the blood stream is the underpinning of the field of endocrinology. The 'father of physiology', Claude Bernard, articulated the concept of internal secretion by describing how the liver produces glucose, which then travels to and is utilized by other tissues in the body. This concept underlies studies on the ovaries, which became a focus of investigation later in the century. In 1896, Emil Knauer, a 29-year-old Austrian, excised the ovaries of adult rabbits and then re-implanted pieces into different locations in the same animals (Watkins 2007 Doisy then enlisted a nurse in the obstetrics clinic to supply each pregnant patient with a 1 gal jug and ask for her urine. This provided the needed material but was fraught with difficulties. Suspected to be a bootlegger because of the large jugs of yellow material in his car, one of Doisy's drivers was nearly arrested until he suggested using the sniff test with the response 'My god, it is urine'. Doisy, then being recruited to St Louis University, continued his efforts to purify the active substance. Each extract was tested with a bioassay and its effect on uterine stimulation. Urine, the material of choice for study, was initially extracted with a very large countercurrent apparatus (Fig. 1). Costing the exorbitan...

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“…For ER-positive breast cancer, dependent on aromatase conversion of precursors to estrogens in postmenopausal women, metformin may inhibit aromatase enzyme expression in breast adipose tissue via AMPK (45). Similar effects on other clinically relevant genes have yet to be explored.…”

Section: Metforminmentioning

confidence: 99%

Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer

Thompson

2014

Clinical Cancer Research

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Metformin, an oral biguanide widely used to treat diabetes, has considerable potential and is in clinical trials as an experimental preventive or therapeutic agent for a range of cancers. Direct actions targeting cellular pathways, particularly via AMP-activated protein kinase and through inhibiting mitochondrial ATP synthesis, or systemic mechanisms involving insulin and insulin-like growth factors have been much studied in vitro and in preclinical models. Epidemiologic and retrospective studies also provide clinical evidence in support of metformin as an antitumor agent. Preoperative window-ofopportunity trials confirm the safety of metformin in women with primary breast cancer, and demonstrate reduction in tumor cell proliferation and complex pathways of gene suppression or overexpression attributable to metformin. Confirmation of insulin-mediated effects, independent of body mass index, also supports the potential benefit of adjuvant metformin therapy. Neoadjuvant, adjuvant, and advanced disease trials combining metformin with established anticancer agents are under way or proposed. Companion biomarker studies will utilize in vitro and preclinical understanding of the relevant molecular pathways to, in future, refine patient and tumor selection for metformin therapy. Clin Cancer Res; 20(10); 2508-15. Ó2014 AACR.

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Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase

Cited by 123 publications

References 18 publications

Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells

Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells

Celebrating 75 years of oestradiol

Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer

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