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[in Menopause - Hormones and Cancer Proceedings]
edited by M. Neves -e-Castro and B.G. Wren 2002
[CH 3 p15-22]

Outline and Commentary on the 2002 Proceedings
by Timothy D. Bilash MD, MS, OBGYN
June 2003

R.B. Clarke and E. Anderson [MHC CH 3]
Clinical Research Department
Christie Hospital
Manchester M20 4BX


  1. Ovarian steroids are essential for the development, proliferation and differentiation of the breast
    1. Early menarch, late menopause increase the breast cancer risk
      1. early menopause protective from breast cancer
      2. pregnancy protective from breast cancer
        1. full lactational differentiation of breast epithelium in response to hormones in pregnancy
    2. breast changes with puberty in humans
      1. primary duct branching
      2. secondary duct branching
      3. terminal duct lobiloalveloar units (TDLU), intial

  2. primary and secondary ducts branching network
    1. double layer of epitehlial cells lining
    2. fibroblast layer
    3. extracellular matrix sourrounding

  3. TDLU (Terminal Duct Lobuloalveloar Unit)
    1. lined by luminal epithelium
    2. surrounded by basal and myoepithelial cells
    3. surrounded by basement membrane
    4. non-pregnant
      1. epithelial proliferation is maximal during the luteal phase (E and P effects from corpus luteum)
    5. during pregnancy
      1. development expands TDLU numbers
    6. after lactation, lobules involute back to non-pregnant appearance
    7. luminal cell is major target for breast tumors

  4. human vs animal studies
    1. in mouse
      1. estrogen induces growth of the ductal system during puberty (ductal elongation)
      2. progesterone stimulates growth of the lobules in pregnancy (ductal side branching and alveolar development)
    2. in human
      1. lobules develop during puberty
      2. maturation in pregnancy and lactation
      3. so rat, human hormone studies may be different

  5. normal human breast epithelium proliferation rates

    1. tissue transplanted into rats
      1. high estrogen stimulates proliferation
      2. there are no obvious effects of progesterone on proliferation
      3. proliferation effects of estradiol and progesterone [see fig 2 p17]
        1. P treatment
          1. Progesterone treatment alone shows very minimal proliferation
        2. low E (follicular level) treatment
          1. LOW Estrogen treatment shows minimal proliferation
          2. these estrogen levels are similar to HRT
        3. hi E (luteal level) treatment
          1. HI Estrogen treatment increases proliferation
        4. hi E+P (luteal level with P) treatment
          1. HI Estrogen plus Progesterone shows same proliferation as HI estrogen only
      4. In summary, a low dose of estrogen equivalent to follicular phase levels induced some proliferation, but higher-dose luteal phase estrogen levels were necessary for a maximum induction of cell division; there were no obvious effects of (natural) progesterone
        1. 5 week trial tho, short term

    2. tissue removed from women

      1. < 5 years HRT of any type had no effect on proliferation rates [p18]
      2. > 5 years of combined HRT correlated with increased proliferation rates
      3. increased breast proliferation correlated with increased breast cancer risk
      4. Er, Pr receptors in normal breast
        1. bind E, P in the nucleus
        2. Er, Pr are transcription factors found within luminal epithelium cells
          1. not in myoepithelium or stroma cells
          2. 96% of cells that express one receptor express both
        3. Era, Erb subsets
          1. 10-15% of epithelial cells are Era, Pr positive
          2. distributed evenly in the interlobular and peripheral alveoli
        4. 2% of epithelial cells are proliferating, but do NOT contain E or P receptors
          1. proliferating (Ki67 antibody-positive) cells do not contain Pr and appear to be a separate population of cells
          2. proliferating cells do not contain Era receptors
          3. proliferating cells often adjacent to or in close proximity to Era positive cells
          4. distinction between steroid receptor positive cells and proliferating cells demonstrated in rats and mice

    3. 2 compartment model in normal breast (Clarke)

      1. hypothesis: steroid receptor-positive cells differentiate from a proliferative stem or transit cell population to act as steroid sensing cells and control cell proliferation via paracrine mechanisms
        1. 1st cells with receptors that sense and secrete hormones
        2. nearby 2nd cells without receptors proliferate due to steroid stimulation

      2. experimental evidence that receptors are not being down regulated during proliferation, but expressed in separate cells

        1. non-proliferating cells
          1. p27 antigen expressed once cells cease to proliferate
          2. expressed in terminally differentiated cells, including steroid receptor-positive cells
          3. Era receptor positive, act as estrogen sensors

        2. proliferating cells
          1. Ki67 antibody-positive
          2. very rarely express p27
          3. Era receptor negative (usually receptor negative)
          4. respond to positive or negative paracrine or juxtacrine factors secreted by Era cells in response to estradiol concentrations

        3. implies steroid secretion and proliferation are mutually exclusive activities in a cell [hormone secretion vs mitogen or growth factor effect]
          1. this separation of steroid receptor expression and proliferation in separate cells is disrupted at an early stage in tumorigenesis
          2. supports that estrogen is the major mitogen (not teratogen) in non-pregnant, premenopausal women
            1. progesterone may be more significant in post menopausal tumors

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