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The Mouse as a Model for Breast Development and Breast Cancer Research. Dr. Tiffany Seagroves Laboratory of Dr. Johnson. tseagrov@biomail.ucsd.edu. BREAST CANCER INTRODUCTION. Statistics Risk Factors Hormones. Breast Cancer Statistics.

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The Mouse as a Model for Breast Development and Breast Cancer Research


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    1. The Mouse as a Model for Breast Development and Breast Cancer Research Dr. Tiffany Seagroves Laboratory of Dr. Johnson tseagrov@biomail.ucsd.edu

    2. BREAST CANCER INTRODUCTION Statistics Risk Factors Hormones

    3. Breast Cancer Statistics • The lifetime probability of being diagnosed with breast cancer for American women is 1 in 8 (NCI, SEER, 1997) AGE IS the MOST IMPORTANT RISK FACTOR Median Age of Diagnosis is Between 60-65 (NIH, 2000)

    4. Recent Decrease in UK and USA Breast Cancer Mortality at Ages 50-69 Years PETO et al. LANCET 355:1822, 2000

    5. Breast Cancer Statistics, cont.(Y-me National Breast Cancer Foundtaion; www.y-me.org) • Most common form of cancer in women, excluding skin cancer • Leading overall cause of death between women of age 40-55 • ACS estimates that 192,000 American women will be diagnosed with breast cancer this year and approximately 46,000 women will die • There are more than 2,000,000 breast cancer survivors in the U.S. today

    6. Factors Associated with an Increased Risk of Breast Cancer [Love et al. 1996] • Age of menarche, first child, onset menopause • Diet, level of exercise, obesity, alcohol consumption • Presence of benign breast disease (DCIS) • Exposure to radiation • Family history and genetics (estimated 5% of total cases can be contributed to genetic factors, and 20-30% cases can be linked to a family history of breast cancer)

    7. Increase in Diganosis of Early-Stage Breast Tumors Since the 1980s

    8. 70% of breast cancers occur in women who have no identifiable risk factors.This is why you are supposed to examine yourself and have yearly exams.

    9. Factors Associated with a Significant Decreased Risk of Breast Cancer (~ 30-50%) • Completed Pregnancy by Age 20 • Exposure to “pregnancy” hormones is protective if happens early • Removal of Both Ovaries by Age 35 • Over time, exposure to “pregnancy” hormones increases risk because ~50% of breast tumors are initially hormone-dependent

    10. Paradox of Hormone Function in the Breast: Why do the same hormones that promote normal development of the breast (to prepare for lactation) act to promote breast cancers later in life?

    11. The Role of “Pregnancy Hormones” in Breast Development and Lactation 1) ESTROGEN AND PROGESTERONE (E+P):Produced by corpeus luteum of ovary first 6 wks or pregnancy, then taken over by placenta. Together, E+P stimulates growth and development of secretory units and ducts in the gland. \ 2) PROLACTIN (Prl): Produced by anterior pituitary Stimulates production of milk

    12. II. ANATOMY AND HISTOLOGY OF THE HUMAN BREAST Whole gland TDLU unit Whole mount and H&E staining

    13. Source: http://mammary.nih.gov

    14. skin Fatty tissue Brown area= “epithelium” Slice of a Whole Human Breast

    15. The Structural Units (Terminal Ductal Lobular Units, TDLU) of the Human Breast Acinar organization 15-yr female 22 yr nulli-parous 30 yr nulli-parous 55 yr parous in menopause 80 yr parous Taken from Cardiif and Wellings, 1999

    16. Human TDLU Whole Mount extralobular terminal ducts acini duct lobules Cardiff website

    17. TDLU Histology: H&E

    18. III. ANATOMY AND HISTOLOGY OF THE MOUSE MAMMARY GLAND Whole Mount H&E Comparative Histology with Human

    19. The Terminal End Bud of the Mouse Mammary Gland TEBs are highly proliferative units that form the ductal network

    20. Stages of Mouse Mammary Development: Whole mounts Alveoli Duct www.mammary.nih.gov

    21. A-B. 6-P, “early” C-D. 10-P, “mid” E-F. 15-P, “mid-to-late” G. Lactation H. 4 days regression

    22. Wellings and Cardiff, 1999 Which is mouse, which is human?(row A vs row B?) A B

    23. IV. WHY THE MOUSE MAMMARY GLAND IS A POWERFUL GENETIC TOOL Reasons Experiment approaches How to make a transgenic mouse to study development/cancer

    24. Why Use the Mouse as a Model for Breast Cancer? • Histology is comparable to human • Can use genetics to manipulate the mammary glands • Have multiple pairs of mammary glands that allow for multiple biopsies • Can purify epithelial cells from the fat and culture them

    25. Mice have 10 Mammary Glands

    26. How to Biopsy a Mouse Mammary Gland

    27. Remove endogenous epithelium from stromal fat pad Transplant a fragment of tissue Containing epithelium from a donor OR inject purified cells Transplanted epithelium grows out Into fat pad in 6-8 weeks Mammary Gland Transplantation

    28. milk protein gene minimal promoter Your Favorite cDNA How To Make a Mammary-Gland Specific Transgenic Mouse usually MMTV or WAP Inject into isolated mouse nucleus Check mammary gland of female progeny for increased expression of your gene

    29. V. WHAT DO MICE HAVE TO DO WITH BREAST CANCER? Differences between breast and mouse mammary tumors How to get mice to develop tumors

    30. Most tumors mouse metastasize to the lung. Most human metastasize to the regional lymph nodes. Mouse tumors have much less fibrosis and inflammation *Half of human breast cancers are hormone-dependent. Most mouse tumors are hormone independent* Molecular lesions causing breast cancer in human have proven to cause breast cancer in mice Similar morphological patterns of lesions appear in both species Development of cancer consistent with multi-hit kinetics Breast cancers in both species are metastatic Breast cancers may be hormone- independent General Differences Between Human Breast and Mouse Mammary Tumors SIMILARITIES DIFFERENCES Taken from Thompson and Cardiff

    31. How to Cause a Mammary Tumor in a Mouse • Treat young mice (time most susceptible) with a chemical carcinogen • Make a transgenic mouse that overexpresses a gene product that regulates growth • Make a “knockout” mouse that deletes a gene that is a tumor suppressor • Breed them several times and watch for spontaneous tumors (rare in mice, more common in rats)

    32. VI. HUMAN BREAST PATHOLOGY Examples of Benign Diseases Tumor Grades/Types Hyperplasia vs Carcinoma

    33. How do pathologists classify and grade breast tumors? Benign vs. hyperplastic vs. carcinoma Well- vs. poorly-differentiated Nuclear morphology- uniform or not Degree of proliferation Ductal or lobular in origin?

    34. Wheel of Prognosis

    35. What factors predict outcome of treatment? • SIZE-the larger the size, fewer patients survive If <2 cm, 11% lymph-node negative patients will have recurrence in 5 yr; >5cm, 25-30% patients will relapse • HISTOLOGIC GRADE-higher the grade, less chance for survival • ER STATUS-loss of estrogen receptor tends to be negatively associated with outcome.In particular women with ER-negative tumors are no longer responsive to tamoxifen, a widely used adjuvant therapy • PROLIFERATIVE RATE -low rate proliferation, increased chances of survival. This factor is also independent of other factors. • Amplification of certain growth factors or receptors or loss of certain tumor suppressors (p53)-lead to decreased survival

    36. Benign Breast Disease 1) Fibroadenoma-overgrowth of stroma Most common benign tumor of the breast; typically occurs in the 20s-30s 2) Cysts-fluid filled epithelium may make breasts feel “lumpy”

    37. MILD SEVERE high power low power Atypical Hyperplasia: Any increase in cell number WITH cytologic changes in cellular morphology, especially nuclear morphology fine needle aspiration low power note different staining intensity of nuclei BUT cells still attached to each other Human Breast Hyperplasias Hyperplasia: Any increase in cell number without cytologic changes in cellular morphology

    38. Solid Cribiform Papillary DCIS (ductal carcinoma in situ): the “precursor” to breast cancer It is in situ or “in place” because the cells are still bound by the extracellular matrix

    39. Well-differentiated Abonormal nuclei from fine needle aspiration of carcinoma still see glandular structures resembling acini Poorly-differentiated arrows point to nuclei with different morphology. Note also cells no longer attached to each other Breast Carcinomas the tumor is invading the breast, it has broken through the matrix mass of cells, no resemblance to acini

    40. Metastasis • Human tumors tend to spread to regional lymph node first (why lymph nodes under arm also biopsied with tumor) • Then tumors spread to small capillaries of the vascular network • Breast tumors tend to metastasize to lung, liver, brain, bone • It is more rare for rodent tumor models to exhibit metastasis, but when observed, are usually restricted to lung Liver mets, (white spots)

    41. VII. MOUSE MAMMARY TUMOR PATHOLOGY Benign Disease Hyperplastic Alveolar Nodules Carcinomas Comparative with Human Tumors

    42. Mouse hyperplasia: the HAN

    43. HANs and Atypical Hyperplasias

    44. Classification of Mouse Mammary Carcinomas: 1) From non-Genetically Engineered Mice (GEM) spontaneous tumors B. tumors as a result of infection of with mouse mammary tumor virus (MMTV) tumors from chemical carcinogen treatment 2) From GEM, usually transgenic mice In contrast to non-GEM, several GEM transgenic mouse models develop tumors with similar pathologies to human breast tumors and more are described every year. examples: TGFa, neu, c-src, myc transgenic mice Classification by Cardiff, 2000

    45. neu (erb-2) myc ras ret-1 different nuclear morphologies from different genes ras myc neu Examples of Mouse Carcinomas more solid more glandular

    46. both MMTV-induced mouse tumors left; DCIS, solid form right; neu transgene left; schirrhous carcinoma right; src transgene left; papillary carcinoma right; a protein kinase transgene

    47. IX. BACK TO HORMONES:HOW DO WE KNOW PREGNANCY CAN BE PROTECTIVE AGAINST BREAST CANCER?

    48. A combination of E+P treatment reduces chemical carcinogen-induced tumorigenesis in rodents (Nandi et al. 1995, 1999)