Targeting Inflammation in Breast Cancer Pathogenesis

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1 Targeting Inflammation in Breast Cancer Pathogenesis Clifford Hudis, M.D. Chief, Breast Cancer Medicine Service Attending Physician, MSKCC Professor of Medicine, Weill Cornell Medical College August 7, 2011

2 Risk Factors for Breast Cancer Gender Age Race Diet high in fat Early onset of menses and late menopause Late or no pregnancies Family history (BRCA1, BRCA2) Dense breast tissue Alcohol consumption Hormone supplementation American Cancer Society. Breast Cancer Facts and Figures

3 Obesity and Breast Cancer Risk factor for development of hormone receptorpositive breast cancer in postmenopausal women. Poor prognostic factor for breast cancer patients regardless of menopause or hormone receptor status. Altered levels of hormones (estrogen, insulin, IGF-1), adipokines (leptin, adiponectin) and proinflammatory mediators (TNFα, IL-1β, PG) contribute to obesity-related breast carcinogenesis.

4 Pathways Linking Obesity with Breast Cancer

5 Obesity, Estrogen and Increased Risk of Postmenopausal Breast Cancer After menopause, peripheral aromatization of androgen precursors in adipose tissue yields estrogen. Increased risk of ER/PR-positive breast cancer in obese postmenopausal women has been attributed, in part, to elevated levels of circulating estradiol. Obesity causes inflammation in visceral and subcutaneous fat. Inflammatory mediators induce aromatase, the rate-limiting enzyme for estrogen biosynthesis. Direct link between obesity breast inflammation aromatase expression was previously unknown.

6 Obesity Causes An Inflammatory State Adapted from Olefsky & Glass. Annu. Rev. Physiol. 2010;72:

7 Hypothesis Obesity induced inflammation will be a/w increased levels of pro-inflammatory mediators (COX-2, TNF-α, IL-1β) leading, in turn, to elevated aromatase expression in breast tissue and visceral fat.

8 Objectives To investigate whether the obesity inflammation aromatase axis is deregulated in the mammary gland and visceral fat in mouse models of obesity. To elucidate the signal transduction pathway that mediates the increased levels of aromatase in obesity. To determine whether obesity is associated with inflammation in the human breast.

9 Diet Induced Obesity: Experimental Design

10 Diet Induced Obesity Causes Focal Inflammation in the Mammary Gland and Visceral Fat

11 Diet Induced Obesity is Associated with Increased Levels of Pro-inflammatory Mediators

12 Levels of Aromatase are Increased in Diet Induced Obesity

13 Obesity Causes Inflammation and Increased Aromatase Levels in the Mammary Gland and Visceral Fat of ob/ob (Leptin Deficient) Mice

14 Diet Induced Obesity Leads to Elevated Levels of Pro- Inflammatory Mediators in the Stromal Vascular Fraction of the Mammary Gland

15 How Does Obesity Increase Aromatase Levels? Lipolysis is increased in obesity. Saturated fatty acids released by adipocytes activate the TLR4 NF-κB pathway in macrophages inducing pro-inflammatory mediators: including TNF-α, IL1-β and Cox-2. Question: Could saturated fatty acid-mediated induction of pro-inflammatory mediators in macrophages induce aromatase in other cell types via a paracrine mechanism?

16 Saturated FA-mediated Induction of Pro-inflammatory Mediators in Macrophages Induce Aromatase in Adipocytes

17 Diet Induced Obesity Causes Elevated Levels of Aromatase and Estrogen-Inducible Target Genes in Adipocytes

18 Conclusions: Mouse Model Obesity caused inflammation in the mammary glands and visceral fat in mice. Increased levels of pro-inflammatory mediators (TNF-α, IL1-β, Cox-2), known inducers of aromatase, were found in the stromal vascular fraction (contains macrophages, endothelial cells, fibroblasts) of the mammary gland which includes macrophages. Increased aromatase levels in both the SVF and adipocyte fractions of the mammary gland suggests a paracrine mechanism involving cross-talk between activated macrophages and other cell types.

20 Next Steps - CSL-B in Humans In obesity, activation of the TLR4 NF-κB pathway in macrophages is likely to be responsible for increased production of pro-inflammatory mediators leading, in turn, to elevated aromatase expression and estrogen synthesis. Hypothesis: Inflammation (CLS-B) occurs in the breast tissue of most overweight/obese women.

21 Study Design Normal breast white adipose tissue was obtained from 30 women who underwent surgery. Routine H&E staining and CD68 IHC was performed.

22 Crown-Like Structures are Common in the Breasts of Overweight and Obese Women % of cases with CLS H&E stain CD68 stain P= /10 6/ /12 Normal Overweight Obese

23 MSKCC : Prospective Tissue Acquisition Women Undergoing Mastectomy N=30 Ipsilateral Invasive Cancer N=2 Contralateral Invasive Cancer N=14 Carcinoma in Situ N=12 No Breast Cancer History N=2 Crown-Like Structures Noted 1/2 Crown-Like Structures Noted 6/14 Crown-Like Structures Noted 7/12 Crown-Like Structures Noted 0/2

24 Severity of Breast Inflammation Correlates with increased BMI

26 Aromatase Correlates With CLS-B

27 Conclusions Inflammation (CLS-B) occurs in the breast tissue of most overweight and obese women. In both obese women and experimental models of obesity, breast inflammation was paralleled by elevated levels of pro-inflammatory mediators (TNF-α, IL-1β, COX-2, PGE 2 ). In obesity, activation of the TLR4 NF-κB pathway in macrophages is likely to be responsible for increased production of pro-inflammatory mediators leading, in turn, to elevated aromatase expression and estrogen synthesis.

28 Next Steps Further exploration of the obesity inflammation aromatase axis to explain the link between obesity and the increased risk of HRpositive breast cancer in postmenopausal women. Development of CLS-B as a biomarker of breast cancer risk or poor prognosis. Interventions (lifestyle, diet, pharmacological) that disrupt the obesity inflammation axis may be useful for reducing the risk of breast cancer.

29 Chronic Inflammation and Cancer Causal Mechanisms Helicobacter pylori and chronic gastritis Epstein-Barr virus Human papillomavirus Hepatitis B or C virus HIV/AIDS Liver flukes (e.g., Clonorchis sinensis) Schistosoma haematobium Gastroesophageal reflux Inflammatory bowel disease Chronic obstructive lung disease Chronic diffuse infiltrative lung disease (e.g., asbestosis, silicosis) Chronic cholecystitis Inflammatory atrophy of prostate Obesity Types of Cancer Stomach cancer Lymphoma Nasopharyngeal carcinoma Anogenital carcinoma Oropharyngeal carcinoma Hepatocellular carcinoma Non-Hodgkin s lymphoma Kaposi s sacrcoma Cholangiocarcinoma Squamous carcinoma of urinary bladder Adenocarcinoma of the distal esophagus Colon cancer Lung cancer Lung cancer Gallbladder cancer Prostate cancer? Breast cancer

Contributors MSKCC Patrick Morris, MD Monica Morrow, MD Dilip Giri, MD Edi Brogi, MD NCI Levy Kopelovich, PhD Support: NCI N01-CN-43302, BCRF, Botwinick-Wolfensohn Foundation, Kochavi BC Prevention

30 Contributors MSKCC Patrick Morris, MD Monica Morrow, MD Dilip Giri, MD Edi Brogi, MD NCI Levy Kopelovich, PhD Support: NCI N01-CN-43302, BCRF, Botwinick-Wolfensohn Foundation, Kochavi BC Prevention Fund, MRC/Beene Center Weill Cornell Andrew Dannenberg, MD Kotha Subbaramaiah, PhD Louise Howe, PhD Tim Hla, PhD Kathy Zhou, PhD Rhonda Yantiss, MD Victoria Blaho, PhD Baoheng Du, MD Priya Bhardwaj, BA

Obesity and Risk of Breast Cancer

Obesity and Risk of Breast Cancer Ayca Gucalp, MD Assistant Attending Memorial Sloan Kettering Cancer Center Instructor of Medicine Weill Cornell Medical College September 5 th, 2014 Case 64 year old postmenopausal